Synthesis of halogenated alkoxyethanes

Abstract

A continuous process for the preparation of halogenated alkoxyethanes of the general formula XClHC-CF2OR, where X is -Cl or -F and OR is C 1-4 and the method comprises the steps of: (i) a compound of the general formula XClC=CF2; (ii) a base; and (iii) C 1-4 The present invention provides a method for the continuous production of halogenated alkoxyethanes, comprising the steps of: introducing reactants including an alkanol into a plate reactor, (a) the plate reactor comprising a fluidic module defining one or more fluidic paths through which the reactants flow as a reaction mixture; and (b) a halogenated alkoxyethane is formed upon mixing of at least the reactants, and the halogenated alkoxyethane so formed exits the plate reactor as a reactor effluent.

Description

[Technical field]

[0001] The present invention relates generally to the continuous preparation of halogenated alkoxyethanes, and in particular to a process for the preparation of halogenated alkoxyethanes, 1-4 The present invention relates to a process for the continuous preparation of halogenated alkoxyethanes of the general formula XClHC-CF2OR, which are alkoxy. [Background technology]

[0002] Halogenated alkoxyethane compounds comprise a significant portion of today's active pharmaceutical ingredients, not to mention pesticides, dyes, flame retardants, and contrast agents.

[0003] The synthesis of halogenated alkoxyethane compounds for use as active pharmaceutical ingredients requires reproducible pharmaceutical grade compounds. Traditionally, halogenated alkoxyethane compounds are produced by batch processes.

[0004] However, batch-to-batch product quality can vary and procedures can require the use of expensive high-pressure equipment. Current batch procedures can suffer from poor and inhomogeneous mixing of reagents and can require long reaction times with relatively low conversion yields. As a result, traditional batch syntheses of halogenated alkoxyethane compounds can require costly post-processing purification procedures to reliably produce pharmaceutical-grade compounds on a commercially relevant scale.

[0005] In contrast to traditional batch procedures, continuous production using semi-batch or semi-continuous configurations is attractive because it can achieve higher yields compared to traditional batch procedures.However, especially in the case of the production of halogenated alkoxyethanes, existing semi-batch or semi-continuous equipment has difficulty in effectively managing toxic and corrosive intermediates and by-products, and cannot adequately address the challenges of traditional batch processes in terms of heat control, safety, waste management, long reaction times, and low conversion yields.

[0006] Thus, there remains an opportunity to ameliorate the problems and limitations associated with conventional synthetic procedures for halogenated alkoxyethane compounds. Summary of the Invention

[0007] The present invention relates to a continuous process for the preparation of halogenated alkoxyethanes of the general formula XClHC-CF2OR, where X is -Cl or -F and OR is C 1-4 and the method comprises the steps of: (i) a compound of the general formula XClC=CF2; (ii) a base; and (iii) C 1-4 introducing reaction components including an alkanol into a plate reactor, (a) the plate reactor comprises a fluidic module defining one or more fluid paths through which reaction components flow as a reaction mixture; (b) a halogenated alkoxyethane is formed upon mixing of at least the reactants, and the halogenated alkoxyethane so formed exits the plate reactor as reactor effluent; The present invention relates to a method for the continuous production of halogenated alkoxyethanes.

[0008] According to the present invention, the reaction components can be continuously introduced into a plate reactor, where they are converted into a reactor effluent containing the desired halogenated alkoxyethane. The effluent leaves the reactor continuously and is available for further processing and / or purification as required. The continuous nature of the process advantageously allows the halogenated alkoxyethane to be produced in commercial quantities.

[0009] In the simplest configuration, a fluid module for use in a plate reactor has a single fluid path connecting the fluid inlet and the fluid outlet of the fluid module. In more complex configurations, a fluid module may have multiple fluid paths connecting one or more fluid inlets and one or more fluid outlets of the fluid module. The multiple fluid paths may merge to effectively mix the respective fluids.

[0010] In some embodiments, the plate reactor comprises multiple fluid modules, which may be connected in series such that a given fluid outlet of a given module is in fluid communication with a given fluid inlet of a subsequent module, providing a continuous fluid path through all modules. In some embodiments, the plate reactor comprises multiple fluid modules connected in parallel. In some embodiments, the plate reactor comprises multiple fluid modules, some of which are connected in series and some of which are connected in parallel.

[0011] The one or more fluid pathways in the fluidic module may have any dimension and design that facilitates the flow of reagent components through the reactor as a reaction mixture. From a design standpoint, the one or more fluid pathways may be in the form of a channel, at least a portion of which has a constant cross-section along a major axis, and / or a channel, at least a portion of which has a variable cross-section along a major axis.

[0012] In the process of the present invention, halogenated alkoxyethanes are produced upon mixing of at least the reaction components. The reaction is exothermic and the heat of reaction can be continuously extracted by any means known to those skilled in the art in the context of plate reactors. Extraction of heat can be achieved by controlling the temperature of each fluid module. In some embodiments, the fluid modules are at a temperature of about -15°C to about 45°C. In some embodiments, the fluid modules are at a temperature of about -10°C to about 25°C. The proposed temperature range has been observed to be particularly advantageous for high yield production of methoxyflurane.

[0013] In some embodiments, the reaction components flow as a reaction mixture through one or more fluid paths at an average flow rate of about 1-15 ml / min. As will be appreciated by one of skill in the art, a particular flow rate will be obtained by an appropriate combination of design and process parameters, which may include the dimensional design of one or more fluid paths, the operating temperature, and the overpressure along the entire fluid path in the plate reactor.

[0014] Flow along one or more fluid paths is characterized by a degree of fluid resistance. The fluid resistance may be quantified in terms of a pressure drop between an inlet and an outlet of one or more fluid paths. For a given design of one or more fluid paths, the pressure drop is then proportional to the flow rate of the reaction mixture along the one or more fluid paths. Typically, the pressure drop is such that the reaction mixture can effectively flow along the one or more fluid paths.

[0015] The pressure in one or more fluid paths may be regulated by any means known to one of skill in the art. For example, the pressure may be regulated by a backpressure valve, a pressure transducer (PT), and / or a backpressure regulation (BPR) system located downstream of the reactor.

[0016] It will be appreciated that the operating characteristics (e.g., pressures, flow rates, dimensions, etc.) of the fluidic modules in the plate reactor of the present invention allow industrial production of halogenated alkoxyethanes, which effectively places the plate reactor in the category of industrial reactors, as opposed to, for example, microfluidic reactors.

[0017] Specific design of one or more fluid paths and process conditions (e.g., temperature and pressure drop, etc.) allows rapid and complete mixing of the reaction components, resulting in significant improvements in reaction time and conversion yield over conventional procedures.

[0018] Furthermore, the one or more fluid paths provide a more controlled reaction environment compared to conventional systems used in batch processes, making the plate reactor of the present invention inherently safer to operate and allowing for the production of purer products compared to conventional equipment. In this regard, extreme conditions of temperature and pressure are easily achieved in the reactor of the present invention, enhancing chemical reactivity while maintaining full control of process parameters.

[0019] Thus, high reaction selectivity and improved safety can be achieved even for the very fast and highly exothermic reactions involved in the formation of the desired halogenated alkoxyethanes. The excellent heat and mass transfer properties afforded by one or more fluid pathways, and the fact that the reaction is resolved along the length of the reaction channel, allow precise control of the residence time of intermediates or products by thermal or chemical quenching of the solutions.

[0020] Furthermore, due to the controlled reaction environment provided by the small section fluid path, the production of hazardous chemicals can be easily controlled. Toxic substances can be easily quenched in-line, thus avoiding unwanted exposure and greatly improving the safety of the process.

[0021] The process of the present invention is also particularly advantageous for the production of commercially relevant halogenated alkoxyethane compounds.

[0022] For example, a compound of the general formula XClC=CF2 may be Cl2C=CF2. In those cases, the method of the present invention involves the production of C 1-4 This method allows for the efficient and scalable production of halogenated alkoxyethane compounds such as methoxyflurane (Cl2HC-CF2OCH3), which can be obtained when the alkanol is methanol. Because of the high reaction yield, pharmaceutical-grade methoxyflurane can be synthesized easily and on a large scale.

[0023] For the production of methoxyflurane, the temperature of the fluidic module (or multiple connected fluidic modules) may be advantageously controlled to a temperature between about −10° C. and about 25° C. In these cases, the reaction mixture may flow across the plate reactor at a flow rate of about 15 ml / min to about 100 ml / min.

[0024] These embodiments may offer an advantageous compromise between good thermal control, safety, short reaction times, high conversion yields, and high scale-up potential for high throughput production of pharmaceutical grade methoxyflurane.

[0025] In some embodiments, the compound of general formula XClC=CF2 is FClC=CF2. In those cases, the method of the present invention comprises the steps of: 1-4 The present invention provides an efficient and scalable production of ClFHC-CF2OCH3, which can be obtained when the alkanol is methanol. The possibility of producing ClFHC-CF2OCH3 in high purity and large quantities is particularly advantageous, since ClFHC-CF2OCH3 is a known precursor in the synthesis of 2-chloro-1,1,2-trifluoroethyl-difluoromethyl ether (enflurane).

[0026] Further aspects and embodiments of the invention are described in more detail below.

[0027] The invention is also described herein with reference to the following non-limiting drawings. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows a first embodiment of a fluidic module of a plate reactor for use in the method of the invention. [Diagram 2] FIG. 2 shows a second embodiment of a fluidic module of a plate reactor for use in the method of the invention. [Diagram 3] FIG. 3 shows a third embodiment of a fluidic module of a plate reactor for use in the method of the invention. [Figure 4] FIG. 4 shows a fourth embodiment of a fluidic module of a plate reactor for use in the method of the invention. [Diagram 5] FIG. 1 shows a 1H nuclear magnetic resonance (NMR) trace recorded on the product fraction extracted at the reactor outlet. [Figure 6] FIG. 13C NMR trace recorded on the product fraction extracted at the reactor outlet. [Figure 7] FIG. 19 shows the 19F MR trace recorded on the product fraction extracted at the reactor outlet. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The method of the present invention relates to a halogenated alkoxyethane of the general formula XClHC-CF2OR, where X is -Cl or -F and OR is C 1-4 A process for the continuous preparation of halogenated alkoxyethanes.

[0030] As used herein, "C 1-4 The term "alkoxy" means a straight or branched chain alkoxy group having 1 to 4 carbons. Examples of straight and branched chain alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and t-butoxy.

[0031] In some embodiments, X is -Cl and OR is a methoxy group, in which case the halogenated alkoxyethane has the formula Cl2HC-CF2OCH3 (methoxyflurane).

[0032] In some embodiments, X is -F and OR is a methoxy group, in which case the halogenated alkoxyethane has the formula FClHC-CF2OCH3. Such compounds are known precursors for the synthesis of 2-chloro-1,1,2-trifluoroethyl-difluoromethyl ether (enflurane).

[0033] The method of the present invention is a method for the continuous preparation of halogenated alkoxyethanes and is based on the use of a plate reactor. The preparation is "continuous" meaning that the halogenated alkoxyethanes are continuously formed as the reagent components are mixed and flow through one or more fluid paths. Thus, the halogenated alkoxyethanes so formed can be collected from the effluent that continuously exits the plate reactor.

[0034] The plate reactor used in the method of the invention comprises one or more fluid paths. The expression "fluid path" is used herein to mean a continuous fluid line through which a fluid can flow. In the context of a plate reactor, said fluid line can be visualized as a channel that fluidically connects the inlet and the outlet of a fluidic module. Thus, a fluid path can have the form of a channel embedded in a solid plate, for example a fluidic module of the type described herein.

[0035] Thus, by "plate reactor" is meant a reactor comprising at least one fluid module, each module having at least one fluid path connecting one or more fluid inlets and one or more fluid outlets of the module. In a typical configuration, a plate reactor is made up of at least one or more planar fluid modules, each defining one or more fluid paths in a planar surface.

[0036] In its simplest configuration, a fluid module has a single fluid pathway providing a fluid connection between one fluid inlet and one fluid outlet. Multiple fluid modules may be connected to one another such that a given fluid outlet of a given module is connected to a given fluid inlet of the next module to provide a continuous fluid pathway through all of the modules. Such connections may be accomplished by suitable fluid connections (e.g., tubing, etc.) known to those skilled in the art.

[0037] Provided that a form of halogenated alkoxyethane is provided, the plate reactor may comprise any number of fluid modules connected to provide one or more fluid paths.

[0038] In some embodiments, the plate reactor comprises one fluidic module.

[0039] In some embodiments, the plate reactor comprises at least two fluid modules. For example, the plate reactor may comprise 3, 4, 5, 6, 7, 8, 9, or 10 fluid modules. In some embodiments, the plate reactor comprises 2 to 10 fluid modules. For example, the plate reactor may comprise 5 fluid modules.

[0040] When the plate reactor comprises multiple connected fluidic modules, the fluidic modules may be connected in series, parallel, or a combination of series and parallel. This makes the scale-up to mass production relatively simple. As a result, the reaction conditions remain unchanged within each fluidic module, so that the scale-up may be performed with minimal or no reoptimization of the reaction conditions. In this regard, it may be more effective and efficient to produce a given amount of halogenated alkoxyethane by simply "increasing the number" of fluidic modules compared to developing a single macrofluidic pathway to produce the same amount of halogenated alkoxyethane. Although the method according to the invention may be implemented to produce small amounts of halogenated alkoxyethane (e.g., a few grams per day) by using one fluidic module, multiple fluidic modules may be easily connected to produce more commercially relevant amounts of halogenated alkoxyethane (e.g., a few grams to several kilos per day) while maintaining the same standards of safety, product purity, reaction time, reaction yield, and safety.

[0041] The plate reactor of the present invention is designed to allow (i) the continuous introduction of reactants into a fluid path through which they flow as a reaction mixture, and (ii) the continuous exit of an effluent containing halogenated alkoxyethanes from the reactor.

[0042] There are no particular limitations as to where the components are mixed relative to the one or more fluid pathways, provided that the reaction components flow through the one or more fluid pathways as a reaction mixture.

[0043] For example, the reaction components may be mixed together to form the reaction mixture prior to being introduced into one or more fluid pathways.

[0044] Thus, in some embodiments, the reaction components are mixed to form a reaction mixture upstream of one or more fluid paths, and the reaction mixture is subsequently introduced into one or more fluid paths. In those cases, the fluidic modules of the producing reactor may be characterized by one or more separate non-intersecting fluid paths through which the reaction mixture flows throughout all modules. In some embodiments, the fluidic modules of the plate reactor comprise a single fluidic path connecting the fluid inlets and fluid outlets of the module. Examples of such modules are shown in Figures 1-2. Multiple modules may be connected to provide a single fluidic path connecting the inlets and outlets of the plate reactor.

[0045] Alternatively, in some preferred configurations, reaction components may be introduced into separate fluid paths through corresponding dedicated inlets and mixed within the module, for example by designing the fluid paths to converge.

[0046] Thus, in some preferred embodiments, the reaction components are introduced into the plate reactor through separate inlets, in which case the fluidic module of the series of modules forming the reactor (or the only module forming the reactor) has converging fluidic paths designed to induce mixing of the reaction components.

[0047] In some preferred embodiments, a fluid module comprises at least two fluid inlets resulting in corresponding fluid paths that merge so that fluids flowing from each fluid inlet mix before reaching the fluid outlet of the module. Examples of such modules are shown in Figures 3 and 4. In these cases, the reactor may comprise one such module, or multiple modules comprising one such module (e.g., the first module in a series).

[0048] The one or more fluid pathways may have any design conducive to the formation of the targeted halogenated alkoxyethane.

[0049] In some embodiments, the fluidic module comprises a fluid pathway in the form of a channel, at least a portion of which has a constant cross-sectional area along the direction of flow, in these instances, opposing interior walls of the channel are essentially parallel to one another.

[0050] In some embodiments, at least a portion of one or more fluid pathways are present as channels having a square or rectangular internal cross-sectional shape with a constant cross-sectional area along the direction of flow. The average internal diagonal of such fluid pathways may range from about 1 to about 12 mm. The average internal diagonal of fluid pathways having a square or rectangular cross-section may typically be 0.2 mm or more and less than 12 mm (and any integers and / or fractions therebetween, e.g., 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, etc.). In one embodiment, the average internal diagonal is 2 mm or more and less than 10 mm. In one embodiment, the average internal diagonal is 2 mm or more and less than 8 mm. In some embodiments, the average internal diagonal is about 6 mm. These dimensions provide a particularly advantageous combination of effective mixing of the reaction mixture and specific surface area for effective thermal control. For example, any of these sized fluid pathways provide a sufficiently large specific surface area for effective thermal control while still being large enough to accommodate a static mixer of the type described herein. As a result, the reactor may be operated to provide a particularly high yield of halogenated alkoxyethanes. The resulting reactor therefore represents an advantageous platform for the large-scale production of pharmaceutical grade halogenated alkoxyethanes.

[0051] FIG. 1 shows an embodiment of a fluidic module 1 having a fluidic path 2 whose major portion has a constant cross-sectional area along the direction of flow. The major portion of the fluidic path 2 appears as a channel with a square or rectangular internal cross-sectional shape, depending on the vertical size of the channel (i.e., perpendicular to the viewing surface). The module 1 comprises inlet / outlet ports 3, 4 through which fluids enter / exit the fluidic path 2. The module of the embodiment of FIG. 1 is suitable for the flow of reaction components, which may flow through the fluidic path 2 as a reaction mixture, mixed upstream of the module. Static mixers 5 in the form of flat baffles are positioned along the fluidic path to aid in the mixing of the reaction components as the reaction mixture flows through the fluidic path.

[0052] In some embodiments, one or more of the fluid paths are in the form of a channel, at least a portion of which exhibits a variable cross-sectional area along the direction of flow.

[0053] For example, a channel may exhibit a cross-sectional area characterized by multiple minima and multiple maxima alternating along the direction of flow. As a result, one or more fluid pathways exhibit periodic constrictions along the direction of flow, which aid in the generation of oscillatory flow. By "oscillating flow" it is meant that the fluid oscillates in the axial direction of one or more fluid pathways such that the fluid flows along the fluid pathways at alternating flow rates. This provides an efficient mixing mechanism whereby the fluid alternates from the walls to the center of the pathway based on the frequency of the alternating cross-sectional restrictions and expansions and the relative spacing of the alternating restrictions and expansions.

[0054] In some embodiments, one or more fluid paths define successive chambers, each having a nozzle-like inlet and a narrowed outlet. One chamber in the series may be nested within the next subsequent chamber, such that the narrowed outlet of one chamber forms the nozzle-like inlet of the next adjacent subsequent chamber. This configuration may be particularly advantageous in that it may provide a tortuous path for fluid flow, further contributing to mixing of reaction components. An example of such a channel design is shown in FIG.

[0055] FIG. 2 shows an embodiment of a fluidic module 1a of a plate reactor for use in the method of the invention. The module 1a defines a fluidic path 2a between fluid inlets / outlets 3a, 4a. The fluidic path 2a defines a series of chambers 6, each having a nozzle-like inlet 7 and a tapered outlet 8. The tapered outlet 8 of each chamber 6 forms the nozzle-like inlet of the next adjacent subsequent chamber. In the illustrated module, the outlets of each chamber 6 are housed within the successive chamber. In this embodiment, each chamber 6 is provided with an internal curved static baffle 9 that can deflect the flow of fluid entering the chamber and follow the curved sides of the chamber that taper towards the outlet 8 of each chamber. The module of the embodiment of FIG. 2 is suitable for the flow of reaction components that are mixed upstream of the module and flow through the fluidic path 2a as a reaction mixture.

[0056] FIG. 3 shows a variation of the embodiment module of FIG. 2. In module 1b of FIG. 3, separate inlets 3b, 3b' give rise to two separate channels 10, 11 that meet at a mixing point 11 to form a nozzle-like inlet of the first chamber 6b. The remainder of the fluid path 2b is similar to that of the module of FIG. 2. The module of the embodiment of FIG. 3 is suitable for mixing two input streams into one stream that flows through fluid path 2b and leaves module 1b at outlet 4b. For example, module 1b may be used to mix a preformed base / alkanol solution with a XClC=CF2 compound to form a reaction mixture that flows through fluid path 2b. The preformed base / alkanol solution may be introduced through inlet 3b and the XClC=CF2 compound may be introduced through inlet 3b'. Alternatively, the preformed base / alkanol solution may be introduced through inlet 3b' and the XClC=CF2 compound may be introduced through inlet 3b.

[0057] In some embodiments, one or more fluid paths have a design that is a combination of the designs described herein. For example, one or more fluid paths may alternate between sections with constant cross-sectional area along the direction of flow and sections with variable cross-sectional area along the direction of flow. The constant cross-sectional area and variable cross-sectional area sections along the direction of flow may be of the type described herein.

[0058] FIG. 4 shows an embodiment module 1c as shown in FIG. 1 having a fluid path 2c that combines a variable cross-sectional area section 13 and a constant cross-sectional area section 14 of the type shown in FIGS.

[0059] Fluidic modules, such as those of the type shown in Figures 1-4, may have any size useful for the efficient production of halogenated alkoxyethanes. For example, the fluidic modules may have lateral dimensions of at least about 100 mm, at least about 250 mm, at least about 500 mm, or at least about 750 mm. In some embodiments, the fluidic modules have lateral dimensions of about 100 mm to about 1 m, e.g., about 100 mm to about 750 mm, about 100 mm to about 500 mm, or about 100 mm to about 250 mm. In some embodiments, the fluidic modules have a square or rectangular shape with dimensions of about 100 x 100 mm to about 750 x 750 mm. In some embodiments, the fluidic modules have dimensions of about 150 x 120 mm, about 300 x 250 mm, about 450 x 300 mm, about 600 x 400 mm, or about 700 x 500 mm.

[0060] In the method of the present invention, the reaction mixture can flow through one or more fluid paths at any flow rate that is conducive to the production of halogenated alkoxyethanes. In some embodiments, the reaction mixture flows through one or more fluid paths at a flow rate of at least about 1 ml / min. For example, the reaction mixture can flow through one or more fluid paths at a flow rate of at least about 5 ml / min, at least about 25 ml / min, at least about 50 ml / min, at least about 100 ml / min, at least about 250 ml / min, at least about 500 ml / min, at least about 750 ml / min, at least about 1 L / min, at least about 2 L / min, at least about 4 L / min, or at least about 8 L / min.

[0061] The one or more fluid pathways may provide any internal volume useful for the production of halogenated alkoxyethanes. For the avoidance of doubt, the "internal volume" of one or more fluid pathways refers to the volume of the internal cavity of the fluid pathway through which the reactants flow as a reaction mixture. In other words, the "internal volume" of one or more fluid pathways corresponds to the total volume of fluids present in the fluid pathway at any time when the reactor is operating.

[0062] In some embodiments, one or more fluid pathways have a total internal volume of at least about 5 ml, at least about 10 ml, at least about 25 ml, at least about 50 ml, at least about 100 ml, at least about 250 ml, at least about 500 ml, at least about 750 ml, at least about 1 L, at least about 1.5 L, or at least about 2 L. For example, one or more fluid pathways may have a total internal volume in the range of 10 ml to 2 L, such as 1 L or less (and any integers and / or fractions therebetween, e.g., 100 ml, 100.1 ml, etc.). In one embodiment, one or more fluid pathways have a total internal volume of 10 ml or more and 1 L or less. For example, one or more fluid pathways may have a total internal volume of 10 ml or more and 500 ml or less. In one embodiment, one or more fluid pathways have a total internal volume of 10 ml or more and 100 ml or less.

[0063] The volumetric residence time of the fluid flowing through one or more fluid paths can be determined by the ratio of the total internal volume of the fluid path to the flow rate of the fluid flowing through the fluid path. The latter can then be determined by the sum of the flow rates of all reagent component lines that converge into one or more fluid paths. In the method of the present invention, the plate reactor can be operated to obtain any residence time of the fluid flowing through one or more fluid paths that is conducive to the production of halogenated alkoxyethanes.

[0064] For example, the plate reactor may be operated to provide a residence time of less than about 250 minutes. In some embodiments, the plate reactor is operated to provide a residence time of less than about 200 minutes, less than about 100 minutes, less than about 50 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, less than about 5 minutes, less than about 2.5 minutes, less than about 2 minutes, or less than about 1 minute. In some embodiments, the plate reactor is operated to provide a residence time of about 1 minute to about 5 minutes.

[0065] For the avoidance of doubt, it will be understood that regardless of the form in which the one or more reagent compounds are provided, they flow through one or more fluid pathways as a liquid reaction mixture. Accordingly, the present invention provides a continuous process for the preparation of halogenated alkoxyethanes of the general formula XClHC-CF2OR, where X is -Cl or -F and OR is C 1-4 and the method comprises the steps of: (i) a compound of the general formula XClC=CF2; (ii) a base; and (iii) C 1-4 It may also be said to provide a continuous process for the production of halogenated alkoxyethanes, comprising the steps of introducing reactants including an alkanol into a plate reactor, (a) the plate reactor comprising a fluidic module defining one or more fluidic paths through which the reactants flow as a liquid reaction mixture, and (b) a halogenated alkoxyethane is formed upon mixing of at least the reactants, and the halogenated alkoxyethane so formed exits the plate reactor as a reactor effluent.

[0066] In some embodiments, the halogenated alkoxyethane is formed by cooling the reaction mixture to a temperature of about -15°C. For example, the reaction mixture can be cooled to about -10°C, to about -5°C, to about -2.5°C, to about -1°C, to about 0°C, to about 5°C, to about 10°C, or to about 25°C. In some embodiments, the halogenated alkoxyethane is formed at a temperature between 0°C and 25°C. For example, the halogenated alkoxyethane can be formed at a temperature of about 10°C.

[0067] The temperature of the reagent compounds may also be controlled to a desired value prior to mixing to form a reaction mixture. For example, the base and / or alkanol may be used at room temperature. In some embodiments, the base and alkanol are provided as a base / alkanol solution. The base / alkanol solution may be used at a temperature below 15° C., such as below 10° C., or between 0° C. and 15° C. In some embodiments, the XClC=CF2 compound is used at room temperature. In some embodiments, the XClC=CF2 compound is used at a temperature below 15° C., such as below 10° C., or between 0° C. and 15° C.

[0068] Thus, in some embodiments, one or more reagent compounds are cooled before being mixed to form a reaction mixture, such that when the reaction mixture is formed, the one or more reagent compounds are in liquid form. Cooling of the reagent components may be necessary to ensure that they are used in a liquid state in the plate reactor. This may be achieved by any means known to those skilled in the art. For example, the reservoirs of either or both the base / alkanol solution and the XClC=CF2 compound may be temperature controlled. In some embodiments, either or both the base / alkanol solution and the XClC=CF2 compound are provided in corresponding temperature-controlled reservoirs. Such temperature control may be achieved by cooling techniques of the type described herein (e.g., cooling jackets, heat exchangers, or combinations thereof). Alternatively, or simultaneously, cooling of one or more reagent components may be achieved by a temperature-controlled reservoir pump, for example, a pump equipped with a cooling system of the type described herein (e.g., cooling jackets, heat exchangers, or combinations thereof).

[0069] As used herein, "room temperature" refers to ambient temperature, for example, from 10° C. to 40° C., but more usually from 15° C. to 30° C. For example, room temperature can be a temperature from 20° C. to 25° C.

[0070] The plate reactor in the process of the present invention can be operated at any pressure conducive to the production of halogenated alkoxyethanes. In the process of the present invention, the reactants can flow through one or more fluid paths at a pressure such that the reaction mixture is kept in liquid form. For example, in the process of the present invention, the reactants can flow through one or more fluid paths at a pressure of about 1,250 kPa (gauge pressure).

[0071] The interior walls of one or more of the fluid pathways that come into contact with the reactants and corresponding mixtures may be made of a material that is chemically inert to the reactants, the halogenated alkoxyethanes, and any reaction intermediates or by-products. In that regard, the material may be the same material that the fluidic modules are made of. Furthermore, the material should have adequate strength and structural integrity to withstand the flow pressures and volumes of the fluids passing therethrough.

[0072] In some embodiments, one or more of the fluid pathways have an interior wall made of a metal, metal alloy, ceramic, or polymer.

[0073] In some embodiments, the fluidic modules that define one or more fluid pathways are made of materials of the types described herein.

[0074] Advantageously, the continuous synthesis of halogenated alkoxyethanes in one or more fluid paths of the type described herein is more efficient than the corresponding synthesis carried out in a batch system according to conventional procedures.In that respect, the behavior of fluids in the type of fluid system described herein is significantly different from the behavior of fluids in a batch environment.While the fluid dynamics in a batch environment is mainly governed by pressure and gravity, in the plate reactor of the present invention, surface tension, energy dissipation, and fluid resistance play an important role in determining the fluid dynamics.In addition, the mixing efficiency brought about by the tortuous nature of one or more fluid paths of the type described herein is superior to that of conventional methods.

[0075] The internal cross-sectional area of ​​one or more fluid pathways can have any shape. Examples of suitable geometries for the internal cross-sectional area include circular, square, rectangular, triangular, or other geometries known in the art.

[0076] The method of the present invention comprises reacting (i) a compound of general formula XClC=CF2, (ii) a base, and (iii) C 1-4The method includes the step of introducing reaction components, including an alkanol, into a plate reactor.

[0077] The compound of general formula XClC=CF2 can be any compound of the formula where X is -Cl or -F. Cl2C=CF2. In some embodiments, X is -F, in which case the compound of general formula XClC=CF2 is FClC=CF2.

[0078] C 1-4 Alkanols promote the addition reaction to the C=C bond of compounds of the general formula XClC=CF2, forming the C bonded to the second carbon 1-4 Any C resulting in an alkoxy group 1-4 In some embodiments, C may be an alkanol. 1-4 The alkanol is selected from methanol (CHOH), ethanol (CHCHOH), 1-propanol (CHCHCHOH), 2-propanol ((CH)CHOH), 1-butanol (CHCHCHCHOH), 2-butanol (CHCHCHCHOHCH), 2-methyl-1-propanol ((CH)CHCHOH), 2-methyl-2-propanol ((CH)COH), and combinations thereof. In some embodiments, C 1-4 The alkanol is methanol.

[0079] The base reacts with the compound of general formula XClC=CF2 under the conditions described herein to form a C 1-4 The base may be any base capable of catalyzing the addition reaction of an alkanol. In other words, the base may be any base capable of catalyzing the addition reaction of an alkanol. 1-4 A base strong enough to produce the corresponding alkoxy ion from an alkanol. For example, C 1-4 When the alkanol is methanol, the base is a strong enough base to produce a methoxy ion.

[0080] In some embodiments, the base comprises an alkali metal base cation. For example, the base can be selected from the group consisting of alkali metals (e.g., Li, Na, and K), alkali metal salts (e.g., carbonates, acetates, and cyanides), alkali metal hydroxides, alkali metal alkoxides (e.g., methylates, ethylates, phenolates), and combinations thereof. For example, the base can be selected from sodium methoxide and potassium methoxide. In some embodiments, the base is an alkali metal hydroxide of the general formula M-OH, where M is an alkali metal selected from the group consisting of Li, Na, and K. In some embodiments, the alkali metal hydroxide is NaOH or KOH. In some embodiments, the base is KOH.

[0081] Preferably, in some embodiments, the base comprises a nitrogen-containing base. For example, an ammonium base. Examples of suitable such bases include tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336), tetraethylammonium hydroxide, and tetramethylammonium hydroxide. In some embodiments, the base is a phosphonium base. For example, the base can be tetramethylphosphonium hydroxide.

[0082] It should be understood that the method of the present invention can be advantageously carried out using a single base, for example, a single base of the type described herein. This is in contrast to using a mixture of different bases, for example, to provide a complex base catalytic system. Thus, in some embodiments, the base used in the method of the present invention is a single base. For example, in some embodiments, the base is one base selected from tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336), tetraethylammonium hydroxide, tetramethylammonium hydroxide, and tetramethylphosphonium hydroxide.

[0083] During the formation of halogenated alkoxyethanes, salt intermediates may precipitate in the fluid pathways. In such cases, precipitation of intermediate salts may result in undesirable blockage of the fluid pathways. Lines would need to be cleaned, leading to undesirable process interruptions. Examples of salt intermediates that may be expected to precipitate during the reaction include salts of alkali metals (e.g., sodium salts, potassium salts), or halide salts (e.g., chlorides, fluoride salts such as Na fluoride or K fluoride). In such cases, a number of strategies may be employed to minimize problems resulting from potential precipitation of salt intermediates.

[0084] For example, the base may be selected to form a salt soluble in the alkanol during the formation of the halogenated alkoxyethane. This advantageously minimizes the formation of insoluble precipitates along the fluid path. As a result, the plate reactor may be operated without interrupting the flow of fluid through the lines for a significantly longer period of time compared to conventional procedures. Furthermore, the frequency and effort of cleaning the lines may be reduced, which may lead to significant cost savings. In this context, intermediate salts are C alkoxyethanes, if the salts do not crystallize and precipitate under the reaction conditions. 1-4 For example, the intermediate salt is C 1-4 If the solubility in the alkanol is at least 0.5% by weight, C 1-4 It may be considered to be "soluble" in the alkanol. Suitable examples of bases capable of forming salts soluble in the alkanol include bases containing ammonium or phosphonium base cations, such as those selected from tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336), tetraethylammonium hydroxide, tetramethylammonium hydroxide, and tetramethylphosphonium hydroxide.

[0085] For example, when the compound of general formula XClC=CF2 is Cl2C=CF2, the base can be an alkylammonium hydroxide, an alkylammonium chloride, or an alkylphosphonium hydroxide. For example, the base can be selected from tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-trioctylammonium chloride, tetraethylammonium hydroxide, tetramethylammonium hydroxide, and tetramethylphosphonium hydroxide. In such cases, the formation and precipitation of salt intermediates can be minimized.

[0086] In some embodiments, the compound of general formula XClC=CF2 is ClC=CF2 (1,1-dichloro-2,2-difluoroethylene), and C 1-4 The alkanol is methanol. In those cases, the method of the invention allows for the efficient and scalable production of halogenated alkoxyethane compounds such as methoxyflurane (Cl2HC-CF2OCH3). This is particularly advantageous since methoxyflurane is the active ingredient in Penthrox®. Penthrox® is an effective, fast-acting short-term analgesic for the initial management of acute traumatic pain and for short-term painful procedures such as wound dressings. Penthrox® is a painkiller used by doctors, the armed forces, ambulance paramedics, sports clubs and surf lifesavers to provide emergency pain relief via an inhalation device known as the "Green Whistle".

[0087] Penthrox® has received regulatory approval in many major jurisdictions around the world and is expected to become widely available as a disposable, single-use inhaler that allows patients (including children) to self-administer the medication under supervision. Current testing is being conducted on an advanced inhaler for self-administration of Penthrox® that will be sold in addition to Green Whistle. The test inhaler was developed as a fully integrated pain relief system that delivers approximately 3ml of Penthrox® to patients in a fast and simple manner. The test inhaler includes a lockout tab, a plunger that activates the inhaler, and a mouthpiece through which the user may inhale the active Penthrox® composition by normal breathing. Once the lockout tab is removed, the inhaler may be activated by depressing the plunger. The inhaler is then set to release the active ingredient through the mouthpiece by the user simply inhaling.

[0088] Penthrox® is intended to be available in facilities worldwide that (i) can provide first aid and emergency services (e.g., hospital emergencies, ambulance services, lifesaving clubs, etc.), (ii) require rapid, point-of-care first aid (e.g., military), and (iii) can sell Penthrox® to the general public (e.g., pharmacies) as a mainstream pain medication of choice.

[0089] Certain process parameters are particularly advantageous for the production of pharmaceutical grade methoxyflurane using a plate reactor of the type described herein.

[0090] For example, it is particularly advantageous to carry out the formation of methoxyflurane at a temperature of about -10° C. to about 25° C. Thus, in some embodiments, the fluidic module is at a temperature of about -5° C. to about 15° C. In some embodiments, the fluidic module is at a temperature of about 10° C.

[0091] In some embodiments, methoxyflurane is produced using a plate reactor that includes a fluid module in which one or more fluid paths define successive chambers, each having a nozzle-like inlet and a narrowing outlet. The chambers of the successive chambers can be nested within the next subsequent chamber, such that the narrowing outlet of one chamber forms the nozzle-like inlet of the next adjacent subsequent chamber. This configuration can be particularly advantageous in that it can provide a tortuous path for the flow of fluid, which can further contribute to the mixing of reaction components.

[0092] In some embodiments, methoxyflurane is produced using a plate reactor comprising a fluidic module having the characteristics described herein, for example, the characteristics of the module shown in any one of Figures 1-4.

[0093] In some embodiments, methoxyflurane is produced using a plate reactor comprising a plurality of fluid modules providing one or more fluid pathways with a total internal volume of at least 10 ml. For example, methoxyflurane can be produced using a plate reactor comprising a plurality of fluid modules providing one or more fluid pathways with a total internal volume of about 10 ml to about 2 L. In some embodiments, the total internal volume is about 20 ml to about 1 L, about 20 ml to about 750 ml, about 20 ml to about 500 ml, about 20 ml to about 250 ml, about 20 ml to about 100 ml, or about 20 ml to about 50 ml.

[0094] Any base may be used, provided that it is in the form of methoxyflurane. Examples of bases suitable for the synthesis of methoxyflurane include bases containing alkali metal base cations. For example, the base may be selected from the group consisting of alkali metals (e.g., Li, Na, and K), alkali metal salts (e.g., carbonates, acetates, and cyanides), alkali metal hydroxides, alkali metal alkoxides (e.g., methylates, ethylates, phenolates), and combinations thereof. For example, the base may be selected from sodium methoxide and potassium methoxide. In some embodiments, the base is an alkali metal hydroxide of the general formula M-OH, where M is an alkali metal selected from the group consisting of Li, Na, and K. In some embodiments, the alkali metal hydroxide is NaOH or KOH. In some embodiments, the base is KOH. In some embodiments, the base contains ammonium or phosphonium base cations. Examples of suitable such bases include tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336), tetraethylammonium hydroxide, tetramethylammonium hydroxide, and tetramethylphosphonium hydroxide.

[0095] In some embodiments, methoxyflurane is produced by providing methanol and a base as a base / methanol solution. The solution may contain about 1% (wt%) to about 10% (wt%) of base based on the total weight of the solution. For example, the solution may contain about 2% (wt%) to about 5% (wt%) of base based on the total weight of the solution. In some embodiments, the base / methanol solution comprises about 2.5% (wt%) of base based on the total weight of the solution. The base / methanol solution may be provided at a temperature of about -5°C to about 10°C.

[0096] The base / methanol solution and Cl2C=CF2 may be mixed in any ratio that leads to the formation of methoxyflurane. For example, the base / methanol solution and Cl2C=CF2 may be mixed according to a volume ratio of 10:1 to 1:1. In some embodiments, the base / methanol solution and Cl2C=CF2 are mixed according to a volume ratio of 5:1. The appropriate volume ratio may be easily obtained by adjusting the flow rates of the base / methanol solution and Cl2C=CF2 when mixing them.

[0097] In some embodiments, the compound of general formula XClC=CF2 is FClC=CF2, C 1-4 The alkanol is methanol. In those cases, the method of the invention provides an efficient and scalable production of ClFHC-CF2OCH3 (2-chloro-1,1,2-trifluoroethyl methyl ether). Since ClFHC-CF2OCH3 is a known precursor in the synthesis of the inhalation anesthetic enflurane (2-chloro-1,1,2-trifluoroethyl-difluoromethyl ether), the possibility of producing ClFHC-CF2OCH3 in high purity and large quantities may be particularly advantageous. According to the reaction sequence assumed in Scheme 1 below, enflurane (b) can be synthesized by chlorinating ClFHC-CF2OCH3 with light (e.g. UV) to give 2-chloro-1,1,2-trifluoroethyl dichloromethyl ether (a), followed by replacement of the chlorine atom on the dichloromethyl group by fluorine. The latter is achieved, for example, by using hydrogen fluoride in the presence of antimony(III) chloride or by using antimony(III) fluoride with antimony(V) chloride.

[0098] [ka]

[0099] In the method of the present invention, the base can be used in any amount that is useful for the formation of halogenated alkoxyethane. In the normal procedure, the base is used in a catalytic amount relative to the compound of the general formula XClC=CF2. By using in a "catalytic amount", the base is used in a substoichiometric amount relative to the compound of the general formula XClC=CF2. In the context of the plate reactor of the present invention, it is understood that a catalytic amount of base relative to the compound of the general formula XClC=CF2 is continuously fed to the plate reactor. In some embodiments, the base to XClC=CF2 compound molar ratio is any fraction of 1. For example, the XClC=CF2 compound molar ratio can be about 0.1:1, about 0.15:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, or about 0.9:1.

[0100] In some embodiments, the base is C 1-4 In these cases, the base / alkanol solution is made up of the base and C 1-4 The base may be present in an amount of 1% by weight to 30% by weight based on the total weight of the alkanol. For example, the base may be a mixture of base and C 1-4 The base may be used in an amount of about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% by weight based on the total weight of the alkanol. 1-4 In some embodiments, the base is used in an amount of about 2.5% by weight based on the total weight of the alkanol. 1-4 In some embodiments, the base is used in an amount of about 5% by weight based on the total weight of the alkanol. 1-4 It is used in an amount of about 2.5% by weight based on the total weight of the alkanol.

[0101] The method of the present invention comprises: (i) a compound of general formula XClC=CF2, where X is -Cl or -F; (ii) a base; and (iii) a compound of general formula XClC=CF2, where X is -Cl or -F. 1-4 It is to be understood that this can be advantageously carried out without the use of additional reactants for the alkanol. (i)-(iii) are reactants of the type described herein.

[0102] For example, in the context of the present invention, 1-4 Alkanols act simultaneously as reagents and solvents, 1-4 It may be said that the reaction proceeds without the need to use an additional solvent other than the alkanol.For example, it will be understood that the method of the present invention can be advantageously carried out without the need to use a solvent that may be conventionally used in the reaction, such as chlorofluoroolefins (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), sulfolane, diethylene glycol dimethyl ether (DG)), or tetraethylene glycol dimethyl ether (TG).

[0103] The present invention therefore relates to a continuous process for the preparation of halogenated alkoxyethanes of the general formula XClHC-CF2OR, where X is -Cl or -F and OR is C 1-4 The method comprises the steps of: (i) a compound of the general formula XClC=CF2, where X is -Cl or -F; (ii) a base; and (iii) C 1-4 Introducing a reaction component consisting of an alkanol into a plate reactor, (a) the plate reactor comprises a fluidic module defining one or more fluid paths through which reaction components flow as a reaction mixture; (b) It may be said to provide a continuous process for the production of halogenated alkoxyethanes, wherein halogenated alkoxyethanes are formed upon mixing of at least the reactants, and the halogenated alkoxyethanes so formed exit the plate reactor as reactor effluent.

[0104] For example, when the method of the present invention is used to produce methoxyflurane, the present invention can be said to provide a continuous process for the preparation of 2,2-dichloro-1,1-difluoro-1-methoxyethane (methoxyflurane), the process comprising the steps of introducing reactants consisting of (i) 1,1-dichloro-2,2-difluoroethene (Cl2C=CF2), (ii) a base, and (iii) methanol into a plate reactor; (a) the plate reactor comprises a fluidic module defining one or more fluid paths through which reaction components flow as a reaction mixture; (b) Methoxyflurane is formed at least upon mixing of the reaction components, and the methoxyflurane so formed exits the plate reactor as reactor effluent.

[0105] Furthermore, when the process of the present invention is used for the production of ClFHC-CF2OCH3, the present invention may be said to provide a continuous process for the preparation of ClFHC-CF2OCH3, the process comprising the steps of introducing into a plate reactor the reaction components consisting of (i) FClC=CF2, (ii) a base, and (iii) methanol, (a) the plate reactor comprises a fluidic module defining one or more fluid paths through which reaction components flow as a reaction mixture; (b) ClFHC-CF2OCH3 is formed at least upon mixing of the reactants, and the ClFHC-CF2OCH3 so formed exits the plate reactor as reactor effluent.

[0106] In the methods of the invention, the reaction components flow through one or more fluid pathways as a reaction mixture. Typically, each reaction component is provided as a separate component, which is mixed to form the reaction mixture. The mixing of the components can be accomplished according to any sequence or means suitable to ensure that the components flow through one or more fluid pathways as a reaction mixture. For example, each component can be provided in a corresponding separate reservoir, extracted therefrom (e.g., pumped thereto), and mixed with the other components to form the reaction mixture. The mixing can be performed according to any suitable mixing sequence.

[0107] In some embodiments, the reaction components are mixed upstream of one or more fluid paths, in which case the fluid introduced into one or more fluid paths is the reaction mixture.

[0108] In some preferred embodiments, reaction components are introduced (e.g., pumped) into separate fluid paths of a fluidic module through corresponding dedicated inlets and mixed by designing the fluid paths so that they meet.

[0109] In some embodiments, the base and C 1-4 The alkanol is provided in a first reservoir as a solution of the type described herein, and the XClC=CF2 compound is provided in a second reservoir. In these cases, the reaction mixture thus comprises (i) the base extracted from the first reservoir and C 1-4 The solution of alkanol is obtained by mixing (ii) with a compound of general formula XClC=CF2 extracted from a second reservoir. The mixing may be performed upstream of one or more fluid pathways, with the mixture subsequently flowing (e.g., pumped) through one or more fluid pathways. Alternatively, in some preferred configurations, the mixing may be performed along one or more fluid pathways, for example by employing a fluidic module that defines a converging fluid pathway.

[0110] XClC=CF2 Compounds, bases, and C 1-4 Arrangement for mixing alkanols (any combination, e.g., XClC=CF2 compound with base and C 1-4 Mixture with a solution of alkanol or XClC=CF2 compound, base, and C as a separate compound 1-4 Alkanol) being accomplished within the fluidic module (eg, by having converging fluid paths) is particularly advantageous for the production of methoxyflurane.

[0111] When the base, alkanol, and XClC=CF2 compound are mixed upstream of one or more fluid pathways, the base, alkanol, and XClC=CF2 compound may be mixed by any means known to one of skill in the art to form a reaction mixture.

[0112] In some cases, the base, alkanol (or base / alkanol solution) and XClC=CF2 compound are mixed by running them through intersecting lines to form a single fluid line, for example in a T or Y configuration. In those cases, the resulting single fluid line can be the source of one or more fluid paths of the plate reactor.

[0113] In yet a further configuration, the base, alkanol (or base / alkanol solution) and XClC=CF2 compound are mixed in a mixing unit located upstream of one or more fluid paths. This can advantageously ensure a high degree of mixing between all reaction components before they enter the fluid paths as a reaction mixture. As a result, rapid formation of high purity arogenated alkoxyethane can be achieved even in the absence of static mixers in the fluid paths.

[0114] The mixing unit may or may not be an integral component of the plate reactor. The mixing unit may be an active mixing unit where mixing is achieved by providing external energy. Examples of such units suitable for use in the method of the present invention include units that provide time-pulsed flow by periodic changes in pumping energy or electric field, acoustic fluid vibration, ultrasound, electrowetting-based droplet vibration, micro-stirrers, etc. In an alternative configuration, the mixing unit may be a passive mixing unit where mixing is achieved by combining the base / alkanol solution line and the XClC=CF2 compound line into one single line. Examples of such devices suitable for use in the method of the present invention include Y- and T-type flow junctions, multi-layered mixers, split-recombine mixers, chaotic mixers, jet impingement mixers, recirculating flow mixers, etc. Typical designs of passive mixing units include T- and Y-flow configurations, interdigital and branching flow distribution structures, focusing structures for flow compression, repeated flow split and recombine structures, flow obstacles in the line, serpentine or zigzag channels, multi-hole plates, small nozzles, etc.

[0115] In some embodiments, one or more fluid paths include an in-line static mixer. This is particularly advantageous to supplement the mixing caused by diffusion of the components as they flow through one or more fluid paths (which can be the primary driver of mixing in fluid paths with small internal cross-sectional areas). Thus, static mixers within the fluid paths can be implemented to induce laminarization of the flowing fluid or the formation of vortices within the volume of the flowing fluid, thereby increasing mixing efficiency.

[0116] Examples of suitable static mixers include baffles, helical mixers, spinning disks, and spinning tubes. As will be appreciated by those skilled in the art, static mixers can be made of any material that is chemically inert to the reactants, halogenated alkoxyethanes, and reaction by-products and / or intermediates. Examples of suitable materials in this regard include polyethylene, polypropylene, polyvinyl chloride, fluorocarbons (e.g., Teflon, polytetrafluoroethylene, polyvinylidene fluoride, fluorinated ethylene propylene, ethylene chlorotrifluoroethylene, polyvinylidene difluoride, perfluoroalkoxyalkanes, etc.), polyetheretherketone, polyethylene, fiberglass reinforced plastics, silicon carbide, silica, Ni-based alloys, No-Mo-based alloys. Those skilled in the art will be able to readily identify other materials suitable for use in static mixers.

[0117] An example of a suitable configuration of a static mixer is provided by the baffle 5 and curved baffle 9 in the fluid module embodiment of Figures 1-4.

[0118] While the above discussion has been made in relation to materials used to make the interior walls of one or more fluid pathways, it will be understood that similar considerations also apply to materials used to make (or line / coat within) elements (or portions thereof) of a system / apparatus used to carry out a method that is expected to come into contact with any of the reactants, products, intermediates, by-products, and / or mixtures thereof. That is, it will be understood that any element (or portion thereof) of a system / apparatus used to carry out a method that is expected to come into contact with any of the reactants, products, intermediates, by-products, and / or mixtures thereof must be made of a material that is chemically inert to said reactants, products, intermediates, by-products (which may include strong acids such as HCl or HF), and / or mixtures thereof. Thus, any such element may be made of (or lined, if desired) with materials of the type described herein.

[0119] For example, any reservoir that is part of a system / apparatus used to carry out a method may be made of (or be lined internally with) a material that is chemically inert to the chemical components or mixtures that the reservoir is intended to store. Similarly, the relevant components of a pump that may be used to pump reactants, products, intermediates, by-products, and / or any mixtures thereof may be made of said reactants, products, intermediates, by-products, and / or any mixtures thereof. Also, the relevant components of a mixing unit of the type described herein that may come into contact with reactants, products, intermediates, by-products, and / or any mixtures thereof may be made of a material that is chemically inert to said reactants, products, by-products, and / or any mixtures thereof. Examples of suitable materials in this regard include polyethylene, polypropylene, polyvinyl chloride, fluorocarbons (e.g., Teflon, polytetrafluoroethylene, polyvinylidene fluoride, fluorinated ethylene propylene, ethylene chlorotrifluoroethylene, polyvinylidene difluoride, perfluoroalkoxy alkanes, etc.), polyether ether ketone, polyethylene, glass fiber reinforced plastics, Ni-based alloys, No-Mo-based alloys. Those skilled in the art will be able to readily identify other materials suitable for use in any of the reactor components to ensure safe handling of all mixtures and compounds involved in the present invention.

[0120] In the methods of the present invention, the relative amounts of reactive components in the reaction mixture can be controlled by adjusting the flow rate of each component as it is mixed with the other components.

[0121] For example, when the base and alkanol are provided as a base / alkanol solution, the relative amounts of the reactants in the reaction mixture can be adjusted by adjusting the flow rate of the base / alkanol solution to the flow rate of the compound XClC=CF2. The ratio of the flow rate of the base / alkanol solution to the flow rate of the compound of general formula XClC=CF2 can be any ratio conducive to the formation of a halogenated alkoxyethane. For example, the reaction mixture can be a mixture of (i) C 1-4The solution of alkanol and base can be obtained by mixing (ii) a compound of general formula XClC=CF2 according to a flow ratio of 1:1 to 10. In some embodiments, the flow ratio is 1:1 to 6:1, 2:1 to 6:1, 3:1 to 6:1, or 4:1 to 5:1.

[0122] In this regard, each of the base / alkanol solution line and the XClC=CF2 compound line may be operated at a flow rate conducive to the formation of halogenated alkoxyethanes upon mixing of the base / alkanol solution with the XClC=CF2 compound. In one embodiment, the flow rate of each line is at least 1 ml / min. For example, the flow rate of each individual line may be at least about 5 ml / min, at least about 25 ml / min, at least about 50 ml / min, at least about 100 ml / min, at least about 200 ml / min, at least about 500 ml / min, at least about 1,000 ml / min, at least about 1,500 ml / min, at least about 2,000 ml / min, at least about 4,000 ml / min, or at least about 8,000 ml / min. In some embodiments, the flow rate of each individual line is about 250 ml / min.

[0123] In some embodiments, the base / alkanol solution is pumped or otherwise provided to the mixer unit or one or more fluid pathways at a flow rate of more than 5 ml / min but less than 8,000 ml / min, and the XClC=CF2 compound is pumped or otherwise provided to the mixer unit or one or more fluid pathways at a flow rate of more than 5 ml / min but less than 8,000 ml / min. In one embodiment, the base / alkanol solution is pumped or otherwise provided to the mixer unit or one or more fluid pathways at a flow rate of more than 50 ml / min but less than 500 ml / min. The XClC=CF2 compound is pumped or otherwise provided to the mixer unit or one or more fluid pathways at a flow rate of more than 50 ml / min but less than 500 ml / min. In one embodiment, the base / alkanol solution is pumped or otherwise provided to the mixer unit or one or more fluid pathways at a flow rate of about 250 ml / min, and the XClC=CF2 compound is pumped or otherwise provided to flow into the mixer unit or one or more fluid pathways at a flow rate of about 50 ml / min.

[0124] In the method of the present invention, the halogenated alkoxyethanes leave the plate reactor as reactor effluent. This can be accomplished by any means known to those skilled in the art. When the plate reactor includes two or more fluid paths, the lines usually converge to form a single outlet through which the effluent leaves the reactor. The effluent can leave the reactor at a flow rate that depends on the operating parameters of the reactor. For example, the reactor effluent containing the halogenated alkoxyethanes can leave the reactor at a flow rate of at least 5 ml / min. In some embodiments, the reactor effluent containing the halogenated alkoxyethanes leaves the reactor at a flow rate of at least 10 ml / min, at least 25 ml / min, at least 50 ml / min, at least 100 ml / min, at least 250 ml / min, at least 500 ml / min, at least 750 ml / min, at least 1 L / min, at least 1.5 L / min, at least 2 L / min, at least 4 L / min, or at least 8 L / min.

[0125] The effluent may contain a certain amount of halogenated alkoxyethane depending on the operating parameters of the reactor. In some embodiments, the reactor effluent contains at least 70% by volume, at least 80% by volume, at least 90% by volume, or at least 95% by volume of halogenated alkoxyethane. Advantageously, the method of the present invention provides a higher conversion yield than conventional procedures. Thus, in some embodiments, the reactor effluent contains at least 90% by volume of halogenated alkoxyethane. In other words, the reactor effluent contains halogenated alkoxyethane with a purity of 70% or more, for example 80% or more, 90% or more, or 95% or more.

[0126] In some embodiments, the method also includes mixing the reactor effluent with a polar liquid. For example, the method may include mixing the reactor effluent with water. This may provide a two-phase mixture that may be used in connection with the purification procedures described herein. The polar liquid (e.g., water) may be mixed with the reactor effluent by any of the mixing procedures described herein. For example, one or more lines carrying the polar liquid (e.g., water) from a reservoir may be made to insert into the reactor effluent line, and the polar liquid may flow (e.g., pumped) from a dedicated reservoir. Alternatively, the polar liquid (e.g., water) may be mixed with the reactor effluent by a mixing unit of the type described herein.

[0127] The polar liquid (e.g., water) may be provided according to any flow rate suitable for obtaining a two-phase mixture with the reactor effluent. Typically, the polar liquid (e.g., water) may be pumped at room temperature.

[0128] The reactor effluent may also contain additional compounds present in the effluent as impurities. Depending on the reactor conditions and / or the nature of the reaction components, the impurities may include one or more reaction by-products and / or one or more unreacted reaction components. The nature of the impurities depends on the reaction conditions and / or the nature of the reaction components. For example, when the method of the present invention is carried out to produce methoxyflurane, the impurities may include methanol, dichlorodifluoroethylene (DCDFE), 2,2-dichloro-1,1,1-trifluoroethane, chloroform, vinyl ethers such as ethers (e.g., methoxyethene (ME), 1,1-dichloro-2-fluoro-2-methoxyethene, halomer (2-chloro-1,1,2-trifluoroethyl methyl ether), orthoesters (OE) such as 2,2-dichloro-1,1,1-trimethoxyethane, methyl dichloroacetate (MDA), chloroform, and HF. In one such embodiment, the impurity comprises 1,1-dichloro-2-fluoro-2-methoxyethene.

[0129] Thus, in some embodiments, the method is for purifying halogenated alkoxyethanes from impurities including one or more of methanol, 2,2-dichloro-1,1,1-trifluoroethane, methyl dichloroacetate, 1,1-dichloro-2,2-difluoroethylene, chloroform, hydrogen fluoride, and orthoesters (OEs) such as methoxyethene (ME), 2,2-dichloro-1,1,1-trimethoxyethane, and methyl dichloroacetate (MDA).

[0130] Depending on the reactor conditions and / or the nature of the reaction components, the impurities may be present in amounts that may range from less than 5% to about 30% by volume of the effluent. Advantageously, the method of the present invention may ensure that halogenated alkoxyethanes may be produced in significantly higher purity (i.e., 90% or more by volume of the effluent) compared to conventional synthesis procedures. In some embodiments, the reactor effluent contains less than 5% by volume of impurities.

[0131] If desired, as part of the process of the present invention, the halogenated alkoxyethane leaving the plate reactor as effluent may be subjected to purification.

[0132] Thus, in some embodiments, the method of the invention comprises: (a) adding one of an amine and an acid to the reactor effluent or to an organic phase separated from the reactor effluent; (b) adding a polar liquid to the mixture obtained in step (a) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (c) adding the other of the amine and acid not used in step (a) to the organic phase obtained in step (b), thereby purifying the halogenated alkoxyethane; The purification step further comprises:

[0133] In this context, a procedure that is a "purification" procedure means that the procedure removes impurities, e.g., impurities of the types described herein, from the reactor effluent or an organic phase separated from the reactor effluent, resulting in a mixture having reduced amounts of impurities compared to the reactor effluent or the organic phase separated from the reactor effluent.

[0134] In some embodiments, the purification procedure includes a step (d) of isolating the purified halogenated alkoxyethane. In step (d), the purified halogenated alkoxyethane may be isolated by any suitable means known to those skilled in the art that results in a halogenated alkoxyethane having a purity of at least 95%, such as about 99.9%, for example at least 99%. Thus, the present invention relates to a halogenated alkoxyethane having the general formula XClHC-CF2OR, where X is -Cl or -F and OR is -C, obtained according to the methods described herein. 1~4 The halogenated alkoxyethane may also be said to be provided, wherein the halogenated alkoxyethane has a purity of at least 99%.

[0135] Thus, in some embodiments, the method of the invention further comprises: (a) adding one of an amine and an acid to the reactor effluent or to an organic phase separated from the reactor effluent; (b) adding a polar liquid to the mixture obtained in step (a) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (c) adding the other of the amine and acid not used in step (a) to the organic phase obtained in step (b), thereby purifying the halogenated alkoxyethane; (d) isolating the purified halogenated alkoxyethane; The purification step further comprises:

[0136] In some embodiments, the purification procedure is performed directly on the reactor effluent.

[0137] In some embodiments, the reactor effluent undergoes further processing before adding the amine or acid. For example, the reactor effluent may first undergo a phase separation procedure. The procedure may include adding a polar liquid (e.g., water) to the reactor effluent to form a two-phase mixture made of a polar phase and a separate organic phase containing the halogenated alkoxyethane. In such a case, the organic phase may be separated from the polar phase and discarded before further processing. The phase separation may be performed as a batch or continuous (e.g., in-line) phase separation.

[0138] Thus, in some embodiments, the method of the present invention further comprises the steps of adding a polar liquid to the reactor effluent to induce phase separation and the formation of a polar phase and a separate organic phase, and separating the organic phase from the polar phase, the organic phase being the organic phase separated from the reactor effluent described in step (a).

[0139] In the context of a purification procedure, the separation of a polar phase from another organic phase in a two-phase mixture can be performed according to any means known to those skilled in the art. For example, the separation can be performed by a gravity separator (e.g., a phase separation flask, tank, or separatory funnel), a superhydrophobic mesh, a superoleophobic mesh, etc. Those skilled in the art will be able to identify appropriate means and procedures to effectively separate the phases of a two-phase mixture.

[0140] As used herein, a "polar liquid" is a liquid substance that can be added to a mixture containing a halogenated alkoxyethane of the type described herein, resulting in the formation of a two-phase mixture including a polar phase and a separate organic phase containing the halogenated alkoxyethane. An example of a suitable polar liquid in this regard is water.

[0141] The purification procedure includes step (a) of adding one of an amine and an acid to the reactor effluent or to an organic phase separated from the reactor effluent. In this step, either the amine or the acid is added to the reactor effluent or to an organic phase separated from the reactor effluent. Thus, in some embodiments, the purification procedure includes adding an amine to the reactor effluent or to an organic phase separated from the reactor effluent. In some embodiments, the purification procedure includes adding an acid to the reactor effluent or to an organic phase separated from the reactor effluent. The amine or acid may be of the type described herein.

[0142] In some embodiments, step (a) of the purification procedure comprises adding an amine to the reactor effluent or to an organic phase separated from the reactor effluent.

[0143] The amine may be a primary or secondary amine.

[0144] Without wishing to be limited to a particular theory, it is believed that amines of the type described herein may react with impurities present in the reactor effluent or in an organic phase separated from the reactor effluent through N-alkylation and / or amidation pathways, which advantageously converts the impurities into compounds that are easier to remove in an isolation step than the starting impurities.

[0145] For example, the synthetic procedures for producing methoxyfluranes of the type described herein may result in the formation of 1,1-dichloro-2-fluoro-2-methoxyethene (vinyl ether) and / or methyl dichloroacetate impurities. In such cases, 1,1-dichloro-2-fluoro-2-methoxyethene (vinyl ether) reacts with primary and / or secondary amines through N-methylation to produce 2,2-dichloroacetyl fluoride. Both 2,2-dichloroacetyl fluoride and methyl dichloroacetate can further react with primary and / or secondary amines through an amidation pathway to produce the corresponding dichloroacetamide. The resulting dichloroacetamide is more easily removed in an isolation step. A schematic of these reactions is shown in Scheme 2.

[0146] [ka]

[0147] Examples of amines suitable for use in the purification procedure include ethylenediamine (1,2-diaminoethane), 1,3-diaminopropane, diethylenetriamine, di-n-propylamine, n-butylamine, ethanolamine, pyrrolidine, 2-aminobutane, and mixtures thereof. In some embodiments, the amine is selected from ethylenediamine, 1,3-diaminopropane, diethylenetriamine, and mixtures thereof.

[0148] In some embodiments, step (a) of the purification procedure comprises adding an acid to the reactor effluent or to an organic phase separated from the reactor effluent.

[0149] Examples of suitable acids include citric acid, hydrochloric acid, sulfuric acid, sulfurous acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, acetic acid, trifluoroacetic acid, nitric acid, nitrous acid, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, and combinations thereof. In one embodiment, the acid is methanesulfonic acid (MSA).

[0150] The acid may be added in any form suitable for promoting effective reaction with impurities present in the reactor effluent or in an organic phase separated from the reactor effluent, for example, the acid may be in the form of an acid solution, such as an aqueous acid solution.

[0151] In some embodiments, the acid is at least a 10%, at least 20%, at least 30%, or at least 40% acid solution.

[0152] In step (a) of the purification procedure, the amine or acid may be added to the reactor effluent or the organic phase separated from the reactor effluent according to any effective amount compatible with the intended purpose. In some embodiments, the amine or acid is added to the reactor effluent or the organic phase separated from the reactor effluent according to a volume ratio of about 0.05:1 to about 2:1 (amine or acid:reactor effluent or the organic phase separated from the reactor effluent). In some embodiments, the amine or acid is added to the reactor effluent or the organic phase separated from the reactor effluent according to a volume ratio of about 0.1:1, about 0.25:1, about 0.5:1, about 1:1, or about 2:1 (amine or acid:reactor effluent or the organic phase separated from the reactor effluent).

[0153] Step (a) of the purification procedure can be carried out in any manner effective to promote the reaction between one or more impurities and the amine or acid, for example, the addition of the amine or acid can be carried out as a batch or continuous procedure.

[0154] The amine or acid is added to the reactor effluent or the organic phase separated from the reactor effluent in step (a) of the purification procedure, and the resulting mixture may be reacted for any time conducive to an effective reaction between one or more impurities and the amine or acid. For example, the mixture obtained in step (a) of the purification procedure may be reacted for at least about 1 minute. In some embodiments, the mixture obtained in step (a) of the purification procedure is reacted for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, or at least about 2 hours. During the reaction, the mixture may be maintained under constant agitation.

[0155] The addition of the amine or acid to the reactor effluent or the organic phase separated from the reactor effluent in step (a) of the purification procedure may be carried out at any temperature conducive to an effective reaction between one or more impurities and the amine or acid. For example, the amine or acid may be added to the reactor effluent or the organic phase separated from the reactor effluent at a temperature of about 10° C. to about 120° C. Higher addition temperatures (e.g., up to 120° C.) may facilitate separation of more volatile impurities. In some embodiments, the amine or acid is added to the reactor effluent or the organic phase separated from the reactor effluent at a temperature of about 10° C. to about 50° C. In some embodiments, the amine or acid in step (a) of the purification procedure is added to the reaction mixture at room temperature. The resulting mixture may be maintained at a temperature conducive to an effective reaction between one or more impurities and the amine or acid. For example, the resulting mixture may be maintained at a temperature of about 10° C. to about 50° C. In some cases, the reaction of the impurity with the amine or acid may be exothermic, in which case, after addition of the amine or acid, a gradual increase in temperature of the resulting mixture may be observed as the amine or acid is added.

[0156] The purification procedure also includes step (b) of adding a polar liquid to the mixture obtained in step (a) of the purification procedure, thereby forming a two-phase mixture made up of a polar phase and a separate organic phase, the separate organic phase containing the halogenated alkoxyethane.

[0157] The polar liquid used in step (b) of the purification procedure may be a polar liquid of the type described herein. For example, the polar liquid used in step (b) of the purification procedure may be water. In those cases, the polar phase of step (b) is an aqueous phase.

[0158] In step (b) of the purification procedure, the polar liquid may be added to the mixture obtained in step (a) of the purification procedure in any amount suitable to induce the necessary phase separation and the formation of a polar phase and a separated organic phase. For example, the polar liquid may be added to the mixture obtained in step (a) of the purification procedure according to a volume ratio of about 0.5:1 to about 2:1 (polar liquid:mixture). In some embodiments, the polar liquid is added to the mixture obtained in step (a) of the purification procedure according to a volume ratio of about 0.5:1, about 1:1, about 1.5:1, or about 2:1 (polar liquid:mixture).

[0159] Once the polar liquid is added in step (b) to the mixture obtained in step (a) of the purification procedure, the resulting biphasic mixture can be maintained under agitation for any period of time conducive to dissolution of polar impurities present in the starting mixture into the polar phase. For example, the resulting biphasic mixture can be maintained under constant agitation for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, or at least about 60 minutes.

[0160] In some embodiments, step (b) of the purification procedure is followed by a step of separating the organic phase obtained in step (b) from the polar phase before further processing. The separation can be carried out according to any procedure known to the skilled artisan suitable for the intended purpose. For example, the separation can be achieved by means of the type described herein. In such a case, the separated polar phase is discarded.

[0161] The purification procedure also includes a step (c) of adding the other of the amine and the acid not used in step (a) to the organic phase obtained in step (b).

[0162] The expression "the other of the amine and acid not used in step (a)" means that if an amine is used in step (a) of the purification procedure, then the acid is used in step (c) of the purification procedure, and conversely, if an acid is used in step (a), then the amine is used in step (c).

[0163] In some embodiments, the purification procedure includes adding an amine to the reactor effluent or to an organic phase separated from the reactor effluent, and then adding an acid to the resulting mixture. The amine or acid can be of the type described herein.

[0164] In some embodiments, the purification procedure includes adding an acid to the reactor effluent or to an organic phase separated from the reactor effluent, and then adding an amine to the resulting mixture. The amine or acid can be of the type described herein.

[0165] Thus, in some embodiments, the purification procedure comprises: (i) adding an amine to the reactor effluent or to an organic phase separated from the reactor effluent; (ii) adding a polar liquid to the mixture obtained in step (i) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (iii) adding the acid obtained in step (i) to the organic phase obtained in step (ii); Includes.

[0166] Thus, in some embodiments, the purification procedure comprises: (i) adding an acid to the reactor effluent or to an organic phase separated from the reactor effluent; (ii) adding a polar liquid to the mixture obtained in step (i) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (iii) adding the amine obtained in step (i) to the organic phase obtained in step (ii); Includes.

[0167] In the embodiments described in the previous four paragraphs, it will be understood that all of the compounds (e.g., amines, acids, and polar liquids) are of the types of compounds described herein, and any procedural conditions are of the types of procedural conditions described herein.

[0168] As will be appreciated by those skilled in the art, the addition of an amine or acid to the organic phase obtained in step (b) may require first separating the organic phase from the polar phase obtained in step (b). For example, when the amine or acid used in step (c) may undergo a dangerous reaction with the polar phase obtained in step (b), it may be necessary to first separate the organic phase and the polar phase. Phase separation may be achieved according to any procedure of the type described herein.

[0169] In step (c) of the purification procedure, the addition of the other of the amine and the acid not used in step (a) of the purification procedure to the organic phase obtained in step (b) of the purification procedure is advantageous to convert impurities that could not be converted in step (a) and / or to remove undesired by-product impurities generated by the reaction promoted in step (a).

[0170] For example, when step (a) of the purification procedure includes adding an acid to the reactor effluent or the organic phase separated from the reactor effluent, the ethane impurity (if present) may be converted to the corresponding chloroacetate salt, which may affect the isolation of the purified halogenated alkoxyethane and cause the formation of additional acidic by-product impurities. This may result in contamination of the final product with chloroacetic acid. For example, under acidic conditions, the by-product 2,2-dichloro-1,1,1-triethoxyethane may be converted to methyl dichloroacetate, as summarized in Scheme 3 below.

[0171] [ka]

[0172] In such cases, the amine subsequently added in step (c) of the purification procedure may react with chloroacetic acid via an amidation pathway to produce the corresponding dichloroacetamide, which is easier to remove in the isolation step.

[0173] In step (c) of the purification procedure, the amine or acid may be added to the organic phase obtained in step (b) according to any effective amount compatible with the intended purpose. In some embodiments, the amine or acid is added to the organic phase obtained in step (b) according to a volume ratio of about 0.05:1 to about 2:1 (amine or acid:organic phase). In some embodiments, the amine or acid is added to the organic phase obtained in step (b) according to a volume ratio of about 0.1:1, about 0.25:1, about 0.5:1, about 1:1, or about 2:1 (amine or acid:organic phase).

[0174] Step (c) of the purification procedure may be carried out in any manner effective to promote the reaction between one or more impurities and the amine or acid. For example, the addition of the amine or acid to the organic phase obtained in step (b) of the purification procedure may be carried out as a batch or continuous procedure.

[0175] In step (c) of the purification procedure, once the amine or acid is added to the organic phase of step (b), the resulting mixture may be reacted for any time conducive to an effective reaction between one or more impurities and the amine or acid. For example, the mixture obtained in step (c) of the purification procedure may be reacted for at least about 1 minute. In some embodiments, the mixture obtained in step (c) of the purification procedure is reacted for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, or at least about 2 hours. During the reaction, the mixture may be maintained under constant stirring.

[0176] The addition of the amine or acid in step (c) of the purification procedure may be carried out at any temperature conducive to an effective reaction between one or more impurities and the amine or acid. For example, the amine or acid in step (c) of the purification procedure may be added at a temperature of about 10° C. to about 120° C. Higher addition temperatures (e.g., up to 120° C.) may facilitate separation of more volatile impurities. In some embodiments, the amine or acid is added in step (c) at a temperature of about 10° C. to about 50° C. In some embodiments, the amine or acid in step (c) of the purification procedure is added at room temperature. The resulting mixture may be maintained at a temperature conducive to an effective reaction between one or more impurities and the amine or acid. For example, the resulting mixture may be maintained at a temperature of about 10° C. to about 50° C.

[0177] Advantageously, the amines or acids used in the purification procedure may react particularly effectively with impurities while remaining inert towards the halogenated alkoxyethanes.

[0178] For example, in a purification procedure to obtain pharmaceutical grade methoxyflurane, the types of amines described herein are particularly effective in selectively reacting with low content impurities (e.g., methyl dichloroacetate) while retaining methoxyflurane. This has been found to be particularly advantageous in purifying methoxyflurane to a purity of greater than 99%, for example about 99.9%.

[0179] In a particularly advantageous purification procedure for methoxyflurane, step (a) of the purification procedure comprises adding an acid to the reactor effluent or the organic phase separated from the reactor effluent, and step (c) of the purification procedure comprises adding an amine to the organic phase obtained in step (b).For example, step (a) of the purification procedure for methoxyflurane can comprise adding methanesulfonic acid to the reactor effluent or the organic phase separated from the reactor effluent, and step (c) of the purification procedure can comprise adding ethanolamine to the organic phase obtained in the purification procedure of step (b).Thus, in some embodiments, the method is a method for the production of methoxyflurane, and comprises a purification procedure comprising adding an acid (e.g., methanesulfonic acid) to the reactor effluent or the organic phase separated from the reactor effluent, and subsequently adding an amine (e.g., ethanolamine) to the mixture obtained.

[0180] Because the amine and acid remain inert toward the halogenated alkoxyethane, the purification procedure can be carried out using an excess of the amine and acid relative to the amount of impurity present in the relevant mixture. Thus, any differences in the level of impurities that depend on the particular synthetic procedure used to prepare the halogenated alkoxyethane can be advantageously accommodated.

[0181] In summary, the purification procedure according to certain embodiments of the present invention can facilitate the removal of impurities from a mixture containing halogenated alkoxyethanes, regardless of the amount of impurities present in the mixture. This is particularly advantageous when the synthesis of halogenated alkoxyethanes is limited by low conversion yields. In those cases, the purification procedure of the present invention can be of great help in providing pharmaceutical grade halogenated alkoxyethanes.

[0182] In some embodiments, the purification procedure includes the step of adding a polar liquid to the mixture obtained in step (c) of the purification procedure. This causes phase separation and the formation of a separate organic phase comprising the polar phase and the halogenated alkoxyethane. In some embodiments, the organic phase may be separated from the polar phase before further processing. The separation may be performed according to any procedure known to the skilled person suitable for the intended purpose. For example, the separation may be achieved by means of the type described herein. In such cases, the separated polar phase is discarded. The separated organic phase may be subjected to drying before further processing. For example, the separated organic phase may be dried using a desiccant. Examples of suitable desiccants in this regard include inorganic desiccants such as magnesium sulfate.

[0183] Thus, in some embodiments of the purification procedure, after adding the polar liquid to the mixture obtained in step (c), the organic phase separated from the polar phase is dried with a desiccant prior to further processing. The desiccant can be magnesium sulfate.

[0184] In some embodiments, the purification procedure further comprises a step (d) of isolating the purified halogenated alkoxyethane, which may be carried out on the dried organic phase obtained from the mixture obtained in step (c) according to a phase separation procedure of the type described herein.

[0185] In step (d) of the purification procedure, the purified halogenated alkoxyethane may be isolated by any suitable means known to those skilled in the art that results in a halogenated alkoxyethane having a purity of at least 95%, such as at least 99%, for example about 99.9%.

[0186] For example, in step (d) of the purification procedure, the purified halogenated alkoxyethane can be isolated by distillation. A person skilled in the art will be able to readily identify suitable distillation conditions that allow isolation of the halogenated alkoxyethane, for example, based on the physical properties of the particular halogenated alkoxyethane and the nature and amount of residual impurities.

[0187] In some embodiments, the isolation of the purified halogenated alkoxyethane in step (d) of the purification procedure is carried out by fractional distillation. These embodiments are particularly advantageous for the isolation of purified methoxyflurane obtained by reacting Cl2C=CF2 with a base of the type described herein and methanol.

[0188] A person skilled in the art would be able to readily identify suitable distillation conditions. For example, the fractional distillation in step (d) of the purification procedure may be carried out at a temperature above the boiling point of the halogenated alkoxyethane. In some embodiments, the distillation is carried out at a temperature above 100°C.

[0189] Thus, in some embodiments, the purification procedure comprises: (i) adding an amine to the reactor effluent or to an organic phase separated from the reactor effluent; (ii) adding a polar liquid to the mixture obtained in step (i) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (iii) adding an acid to the organic phase obtained in step (ii); (iv) isolating the purified halogenated alkoxyethane; Includes.

[0190] In some alternative embodiments, the purification procedure comprises: (i) adding an acid to the reactor effluent or to an organic phase separated from the reactor effluent; (ii) adding a polar liquid to the mixture obtained in step (i) to induce phase separation and formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (iii) adding an amine to the organic phase obtained in step (ii); (iv) isolating the purified halogenated alkoxyethane; Includes.

[0191] In some embodiments, the purification procedure comprises a series of steps of the type described herein. Thus, in some embodiments, the distillation procedure comprises: (i) adding a polar liquid to a reactor effluent containing the halogenated alkoxyethane to induce phase separation and formation of a polar phase and a separate organic phase containing the halogenated alkoxyethane; (ii) separating the organic phase obtained in step (i); (iii) adding one of an amine and an acid to the organic phase obtained in step (ii); (iv) adding a polar liquid to the mixture obtained in step (iii) to induce phase separation and formation of a polar phase and a separate organic phase containing the halogenated alkoxyethane; (v) separating the organic phase obtained in step (iv); (vi) adding the other of the amine and acid not used in step (iii) to the organic phase obtained in step (v); (vii) adding a polar liquid to the mixture obtained in step (vi) to induce phase separation and formation of a polar phase and a separate organic phase comprising the halogenated alkoxyethane; (viii) separating the organic phase obtained in step (vii); (ix) drying the organic phase obtained in step (viii); (x) distilling the organic phase obtained in step (ix) by fractional distillation, thereby isolating the purified halogenated alkoxyethane; Includes.

[0192] It will be understood that all compounds and procedural conditions of steps (i) to (x) listed in the preceding paragraph are of the type of compounds and procedural conditions described herein. The embodiment of the purification procedure having the sequence of steps (i) to (x) is particularly advantageous for the purification of methoxyflurane obtained by reacting Cl2C=CF2 with a base and methanol of the type described herein.

[0193] Certain embodiments of the present invention will now be described with reference to the following non-limiting examples. EXAMPLES

[0194] [Example 1] A batch solution of potassium hydroxide (2.5% w / v) in methanol (1000 ml) was prepared, cooled in ice and used as "material 1". 1,1-Dichloro-2,2-difluoroethylene (DCDFE, 200 ml) was used as "material 2".

[0195] A commercially available plate reactor with five fluid modules connected in series was used to provide a total reaction volume of 45 ml. Plate reactors can be purchased from any of the commercially available sources, such as Corning's AFR reactors, or Chemtrix glass or ceramic reactors.

[0196] Material 1 was introduced into the inlet of the first fluidic module at a flow rate of 10 ml / min and material 2 was introduced into another inlet of the fluidic plate at a flow rate of 2 ml / min. The temperature of the fluidic modules was controlled at 10°C.

[0197] A total of 80 ml of DCDFE was passed through the reactor and operated at steady state to give a residence time of the reaction mixture of 3.75 min. The effluent was collected in fractions and after separation and drying the product was obtained as a clear colorless liquid. Final combined volume = 80 ml (113.6 g, molar yield = 80%, purity 97%).

[0198] Scheme 4 below illustrates the hypothesized mechanism involved in the formation of impurities upon further reaction of methoxyflurane.

[0199] [ka]

[0200] The impurities from the organic phase obtained by the procedure of Example 1 were mainly made up of methoxyethene (ME) impurity.

[0201] Gas chromatography (not shown) confirmed the formation of methoxyflurane. The compositions of the subsequent fractions of the separated product are reported in Table 1 below. All fractions contained greater than 96.9% methoxyflurane (MEOF) with traces of chloroform, orthoester (OE), and methoxyethene (ME) impurities, as well as fractions of unreacted methanol and DCDFE. This level of purity was superior to that obtained under batch reaction conditions, which typically feature a reaction product purity of about 65%.

[0202] [Table 1]

[0203] NMR was also performed on fraction 4 listed in the table, and the results shown in Figures 5 to 7 were obtained. 1 Related to the H trace, Fig. 6 13 Related to the C trace, Fig. 7 19 Related to F trace.

[0204] [Example 2] (Refining process) (Removal of Methoxyethene (ME) and Orthoester (OE) Process Impurities) Approximately 77 ml (110 g) of the crude reaction product from Example 1 was transferred to a 3N 250 ml RBF equipped with a magnetic stirrer and a thermometer at ambient temperature (recorded at 20° C.). 9.5 ml of methanesulfonic acid was added slowly to the mixture over approximately 1 minute with stirring. The resulting mixture was stirred for 120 minutes, at which point 15 ml of water was added to the stirred mixture and stirred for an additional 60 minutes. The suspension was transferred to a separatory funnel, thereby removing the organic layer from the aqueous layer. The organic layer was transferred back to the 3N 250 ml RBF and labeled Crude B.

[0205] (Removal of methyl dichloroacetate (MDA)) 7.7 ml of ethanolamine was added slowly to the Crude B mixture with stirring at ambient temperature for approximately 1 minute. The resulting mixture was left stirring for approximately 30 minutes. At this point 25 ml of water was added and stirring was stopped to allow the suspended phases to separate. The suspension was transferred to a separatory funnel and the organic layer was removed from the aqueous layer. The organic phase was dried over magnesium sulfate and sampled for purity. The final volume of the resulting mixture (Crude C) was 71 ml (100.8 g, molar yield=70%, purity>99%, max 99.9%).

[0206] As used herein, the term "about" when referring to numerical values ​​can encompass a variation from the particular numerical value, in some embodiments, of ±20%, in some embodiments, of ±10%, in some embodiments, of ±5%, in some embodiments, of ±1%, in some embodiments, of ±0.5%, and in some embodiments, of ±0.1%.

[0207] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprises" and variations such as "include" and "comprising" will be understood to mean the inclusion of a stated integer, step or group of integers but not the exclusion of other integers, steps or groups of integers or steps.

[0208] Reference in this specification to a prior publication (or information derived therefrom), or to known matter, is not, and should not be construed as, an approval or validation of, or in any way an indication that, that prior publication (or information derived therefrom), or that known matter forms part of the common general knowledge in the field to which this specification pertains.

[0209] Many modifications will be apparent to those skilled in the art that do not depart from the scope of the invention.

Claims

1. A continuous preparation method of halogenated alkoxyethane of general formula XClHC-CF ２ OR, wherein X is -Cl or -F, and OR is C １－４ alkoxy, and the method comprises the step of introducing reaction components including (i) a compound of general formula XClC=CF ２ , (ii) a base, and (iii) C １－４ alkanol into a plate reactor, (i) The plate reactor comprises a fluid module defining one or more fluid paths through which the reaction components flow as a reaction mixture, (ii) The halogenated alkoxyethane is formed at least when the reaction components are mixed, and the halogenated alkoxyethane thus formed flows out of the plate reactor as a reactor effluent, A continuous production method of halogenated alkoxyethane of general formula XClHC-CF ２ OR.

2. The method according to claim 1, wherein the plate reactor comprises a stack of fluid modules defining the one or more fluid paths through which the reaction components flow as a reaction mixture.

3. The method according to claim 1 or 2, wherein the fluid module is at a temperature of about -15°C to about 45°C.

4. The method according to claim 1 or 2, wherein the one or more fluid paths provide a total internal volume of at least 10 ml.

5. The method according to claim 1 or 2, wherein the reactor effluent contains at least 90% by volume of the halogenated alkoxyethane.

6. The method according to claim 1 or 2, wherein the plate reactor provides a residence time of less than about 5 minutes.

7. The reaction mixture is (i) a solution of C １－４ alkanol and a base and (ii) a compound of general formula XClC=CF ２The method according to claim 1 or 2, obtained by mixing with the compound of

8. The method according to claim 1 or 2, wherein the mixing is carried out upstream of the one or more fluid paths.

9. The mixing is carried out by combining (i) the flow of the solution of the C １－４ alkanol and the base with (ii) the flow of the compound of the general formula XClC═CF ２ in a flow rate ratio of 1:1 to 10:1, the method according to claim 1 or 2.

10. The base is used in an amount of 1% to 30% by weight based on the total weight of the base and the C １－４ alkanol, the method according to claim 1 or 2.

11. The compound of the general formula XClC═CF ２ is Cl ２ C═CF ２ or FClC═CF ２ , the method according to claim 1 or 2.

12. The C １－４ alkanol is methanol (CH ３ OH), ethanol (CH ３ CH ２ OH), 1-propanol (CH ３ CH ２ CH ２ OH), 2-propanol ((CH ３ ) ２ CHOH), 1-butanol (CH ３ CH ２ CH ２ CH ２ OH), 2-butanol (CH ３ CH ２ CHOHCH ３ ), 2-methyl-1-propanol ((CH ３ ) ２ CHCH ２ OH), 2-methyl-2-propanol ((CH ３ ) ３The method according to claim 1 or 2, selected from COH) and combinations thereof.

13. The halogenated alkoxyethane is Cl ２ HC-CF ２ OCH ３ (methoxyfuran) or ClFH-CF ２ OCH ３ The method according to claim 1 or 2.

14. The method according to claim 1 or 2, wherein the base contains an alkali metal base cation or an ammonium base cation.

15. The method according to claim 1 or 2, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, tetrabutylammonium hydroxide, benzyl(trimethyl)ammonium hydroxide, N-methyl-N,N,N-tri octylammonium chloride, tetraethylammonium hydroxide, tetramethylammonium hydroxide, tetramethylphosphonium hydroxide.

16. (a) adding one of an amine and an acid to the reactor effluent or the organic phase separated from the reactor effluent; (b) adding a polar liquid to the mixture obtained in step (a) to induce phase separation and the formation of a polar phase and a separate organic phase, the organic phase containing the halogenated alkoxyethane; (c) adding the other of the amine and the acid not used in step (a) to the organic phase obtained in step (b), thereby purifying the halogenated alkoxyethane; The method according to claim 1 or 2, further comprising a purification procedure comprising:

17. The method according to claim 16, further comprising step (d) of isolating the purified halogenated alkoxyethane.

18. The method according to claim 16, wherein the amine is selected from ethylenediamine (1,2-diaminoethane), 1,3-diaminopropane, diethylenetriamine, di-n-propylamine, n-butylamine, ethanolamine, pyrrolidine, 2-aminobutane, and mixtures thereof.

19. The method according to claim 16, wherein the acid is selected from hydrochloric acid, sulfuric acid, sulfurous acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, acetic acid, trifluoroacetic acid, nitric acid, nitrous acid, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, and combinations thereof.

20. The method according to claim 16, wherein the purified haloalkoxyethane is isolated by fractional distillation.

21. The method according to claim 16, wherein the polar liquid is water.

22. The method according to claim 16 for purifying a haloalkoxyethane from impurities comprising one or more of methoxyethene (ME), orthoester (OE), and methyl dichloroacetate (MDA).

23. X is -Cl or -F, OR is C １－４ alkoxy, and the haloalkoxyethane is a haloalkoxyethane of the general formula XClHC-CF ２ OR obtained according to the method according to claim 16 and having a purity of at least 99%.

Images