GB2587294A - Processes for the preparation of desflurane - Google Patents

Abstract

A method for the manufacture of desflurane, comprising the steps of; providing isoflurane dissolved in supercritical CO2; reacting the isoflurane dissolved in supercritical CO2 with a fluorine donor at temperatures at or above the critical temperature of CO2 and at pressures at or above the critical pressure of CO2. The fluorine donor may comprise potassium fluoride, sodium fluoride, anhydrous fluorine or gaseous fluorine. The reaction mixture may be passed through a reaction chamber containing a catalyst, wherein the catalyst may be selected from an antimony pentahalide, a transition metal trifluoride, a transition metal oxide or a phase transfer catalyst. The catalyst may be in particular selected from cobalt trifluoride, chromia or tetramethylammonium chloride. A system for the manufacture and purification of desflurane from isoflurane using a fluorine donor in which the reaction is conducted in supercritical CO2 is also disclosed. A method for synthesis of desflurane by the fluoro-substitution of isoflurane is also disclosed.

Description

PROCESSES FOR THE PREPARATION OF DESFLURANE

Technical Field

The present invention relates to methods and improvements in the synthesis of the valuable anaesthetic agents Sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane) and Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) with improved yield and use of reactants and products by the use of supercritical carbon dioxide as a co-solvent

Background

Halogenated ethers are important agents for the delivery of anaesthesia via inhalation. Included among these anaesthetics are Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether-CF3 CHFOCHF2), Isoflurane (2-chloro-2-(difluoromethoxy)-I, I, I -trifluoro-ethane- CF3 CHCIOCHF2) and Sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane- (CF3)2 CHOCH2 F).

Each anaesthetic agent has subtly different physiochemical properties that lead to different characteristics in their use as anaesthetic agents. Sevoflurane is sweet-smelling and therefore used for gas induction of anaesthesia. Desflurane has a low blood-gas solubility coefficient and therefore has a rapid onset and offset of action, even after periods of prolonged use. However, it is highly irritable to the airways, leading to coughing and laryngospasm. Therefore it cannot be used for gas induction of anaesthesia.

US patent No's US 3,683,092 (1970) and US 3,689,571 (1972) specify the use of sevoflurane as an anaesthetic agent and three main mechanisms of manufacture.

Firstly, the chlorination of 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether by a photo-induced reaction of 0.5-1:1 molar quantities of chlorine to hexafluoro-Z-methyl ether to form a chloromethyl ether. The chlorine is then replaced fluorine in the methyl group by adding the molar excess potassium fluoride in a mutual high boiling point solvent, sulfolane, at 120.0 or by using bromine triflouride. US patent No 5,886,239 (1997) states that chloromethyl 2,2,2-trifluoro-I -(trifluoromethyl)ethyl ether (chlorosevoether) can be reacted with sterically hindered tertiary amine hydrofluoride salts using chlorosevoether in molar excess rather than sulfolane as solvent. This was improved in US 8,729,313 by the use of sevoflurane itself as the solvent instead of a molar excess of chlorosevoether.

A second process in US 3,683,092 is the reaction of 1,3-polyfluoro-2-propanol, formaldehyde and hydrogen fluoride. Further methods based around US patent no 4,250,334 (1979) use the reaction of hexaflouroisopropanol (HFIP) with formaldehyde or trioxane, in the presence of hydrogen fluoride and an acid and dehydrating agent (fluorosulphonic acid/sulphuric acid or aluminium tetrafluoride). The difficulties with switching a fluorine for hydrogen are mitigated by US Patent no 6,100,434 which claims the reaction of hexafluoroisopropanol with trioxide or paraformaldehyde in the presence of a chlorinating catalyst, alumium trichloride. This produces sevochlorane, which is then has the chlorine substituted for fluorine by reaction with potassium fluoride in the presence of a potassium base (Potassium carbonate) dissolved in a solvent such as polyethylene glycol (PEG) at a temperature of 85-95 degrees Centigrade.

Water is added as a lewis base to reduce the breakdown of sevochlorane by the reaction product alumium hydroxydichloride, which ultimately needs to be removed from the process and recycled back to aluminium trichloride.

This invention relates to the use of supercritical carbon dioxide as a solvent in both processes described above. Carbon dioxide (CO2) has a critical pressure of 7.39MPa and critical temperature of 31.1 degrees centigrade. When above critical pressure and temperature, it exists as a supercritical fluid. Supercritical fluids have no surface tension and the properties of both a liquid and a gas. They expand to fill the container they are in but also have a density-dependent ability to dissolve substances like a liquid. Supercritical CO2 is a non-polar solvent, but may be able to dissolve some polar compounds by the use of a modifier such as methanol. Halocarbons including the fluoroether anaesthetic agents such as Desflurane, Sevoflurane and Isoflurane are highly soluble in supercritical CO2 as they are non-polar. The concentration of reactants can be varied in proportion to CO2. Furthermore, temperatures and pressures above the critical temperature and pressure of carbon dioxide can be used with dilution to control reaction rate. Therefore, supercritical CO2 is an ideal reaction solvent for the formation of the above mentioned fluoroethers.

One further advantage to the use of supercritical carbon dioxide is that it can readily be used in currently available systems as a mobile phase in supercritical fluid chromatography. Supercritical chromatography is able to separate out reactants and products by their different retention-times in columns based on polarity (dipole or hydrogen-bonding), diffusivity or size-exclusion. Detection systems based on ultraviolet (UV), Infra-red (IR) absorbance spectra, mass spectrometry (MS), photoacoustic spectroscopy (PAS) or acoustic resonance spectroscopy (ARS) can be used to detect individual compounds as they leave the column and separate them by influencing the position of valves by a computerised controller. In this invention, these methods can be used to remove unwanted products and return desired reactants to the reaction vessel. If further reactants are added as required, a continuous reaction can be developed, in which the desired product is removed and collected, useful reactants are returned to the reaction vessel in the correct quantities, and unwanted products are removed for further processing.

The final advantage of supercritical CO2 is its use as a gaseous mobile phase during depressurisation below critical pressure to drive fractionation of volatile compounds by their volatility. The supercritical mixture of carbon dioxide and volatile compound is depressurised (to any subcritical pressure) and heated to prevent freezing at the back pressure regulator, vaporising both the carbon dioxide and any volatile product. This product can then be passed to an expansion vessel and fractionating column set at subcritical pressure and the desired temperature to condense a single volatile fraction but leave more volatile fractions in gaseous form to be selected in further columns or returned to the expansion vessel for multiple cycles to ensure fraction separation.

In this invention, sevoflurane ((CF3)2 CHOCH2 F) can occur via two methods, both using supercritical CO2 as the solvent.

In the first embodiment, chlorosevoether (chloromethyl 2,2,2-trifluoro-I - (trifluoromethyl)ethyl ether dissolved in supercritical CO2 is reacted with a sterically-hindered tertiary amine hydrofluoride salt at temperatures above the critical temperature of CO2 (31.1 degrees C) and pressures above the critical pressure of CO2 (7.39MPa) in a reaction chamber fed by a pump supplying CO2 from a cylinder via an accumulator. A flow of supercritical CO2 from the pump maintains the pressure in the chamber as the supercritical mixture is withdrawn from the chamber to be passed through chromatography columns, fractional separation unit or both systems combined. Chromatography and/or fractional separation are used to remove unwanted products, collect the desired product and return useful reactants to the reaction chamber via a pump. Further reactants are added as required by an injection system. The concentration of reactants and products is continuously measured by the use of UV, IR, MS or PAS or ARS, influencing the flow of supercritical CO2, temperatures and pressures of the reaction and the addition of reactants.

This first embodiment has the advantages of using an environmentally friendly solvent that is able to control the reaction rate by varying dilution, temperature and pressure as the reaction proceeds. Furthermore, by combination with chromatography and fractional separation systems, wanted products and reactants can be selectively captured or re-used and unwanted products removed. Finally, the flow of the supercritical solution through the process allows sampling of the concentrations of the reactants and products so that the optimal reaction conditions can be maintained and further reactants added as required.

In the second embodiment, a mixture of hexaflouroisopropanol (HFIP) with equimolar or excess molar concentrations of paraldehyde or trioxane are dissolved in supercritical CO2 in a chamber fed by a CO2 cylinder and pump. These reactants are then passed under the flow of supercritical CO2 to a chamber containing aluminium trichloride. As the reactants flow through the second chamber, they form sevochlorane. The flow of CO2 is determined to ensure adequate conversion to sevochlorane, but minimal breakdown of the sevochlorane by aluminium hydroxydichloride. The supercritical mixture passes to a second reaction chamber in which potassium fluoride is added with or without water to replace the chlorine with a fluorine, forming sevoflurane. The temperature of the second reaction chamber may be different from the first chamber, but must be above the critical temperature of carbon dioxide. The supercritical mixture passes into a multi-column chromatography system, fractional separation system or both to allow the separation of different reactants or products.

Sevoflurane can be purified and collected and reactants recycled to their respective reaction chambers. Purified carbon dioxide can be re-pressurised and re-used.

This second embodiment uses supercritical CO2 as a preferred solvent to sevochlorane or sevoflurane. This enables a faster reaction time and reduced breakdown of sevochlorane and sevoflurane by the alumium hydroxydichloride. Furthermore, the sevochlorane exposure-time to the alumium trichloride/aluminium hydroxydichloride can be controlled. The aluminium hydroxydichloride chamber can then be re-activated by converting aluminium hydroxydichloride to aluminium trichloride when outside of the preferred system.

Supercritical CO2 is an ideal solvent for the fluorination of the sevochlorane by potassium fluoride, preventing product breakdown. Finally, supercritical chromatography and/or fractionation driven by CO2 depressurisation can be used to recycle useful reactants, purify the product and remove unwanted products under monitoring by UV, IR, MS, PAS or ARS.

Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether-CF3 CHFOCHF2) is synthesised by the fluoro-substitution of isoflurane (2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane). This can be carried out by elemental fluorine in a fluorinated solvent (Freon E3) or in fluorine gas in argon at cryogenic temperatures as in US patent 3,897,502, however the use of elemental fluorine is hazardous. US Patent no 6,054,62 uses transition metal fluorides. preferably cobalt but suffers from poor yield and by-product formation. US Patent No. 6,800,786 shows the reaction of isoflurane with optimum quantities of hydrogen fluoride in the presence of an antimony pentachloride catalyst. US Patent number 20060205983 Al states the use of antimony pentafluoride to reduce the molar excess of hydrogen fluoride. Both antimony pentafluoride and pentachloride are expensive catalysts that are discarded after use.

EP 341,005B details the reaction of isoflurane with sodium or potassium fluoride at high temperatures (278 degrees C) and pressures of 500psi in the absence of a solvent over a long period of time. This is a batch process and requires a long reaction time. GB 2,2I9,292A specifies the reaction of isoflurane with an alkali metal fluoride in sulpholane in the presence of a phase transfer catalyst at 210 degrees C. In the third embodiment of this invention, isoflurane is dissolved and diluted in supercritical CO2 at supercritical temperatures and pressures and supplied by a CO2 cylinder and pump.

Potassium fluoride, sodium fluoride or anhydrous fluorine are added to the mixture at concentrations that control the exothermic nature of the reaction. Alternatively gaseous fluorine can be added to the carbon dioxide. When compressed above the supercritical pressure of CO2, fluorine itself is in a supercritical state. As supercritical fluids dissolve each other perfectly, this would be an ideal reaction mixture. If the reaction rate is too slow at or just above the critical temperature of CO2 (31.1 degrees C), the reaction mixture can be passed through a reaction chamber containing antimony pentahalide, a transition metal trifluoride (for example cobalt trifluoride), transition metal oxide (such as chromia) or mixed with a phase transfer catalyst such as tetramethylammonium chloride to reduce the temperature required for the reaction to proceed without requiring high temperatures that may cause an increase in the cleavage of the carbon-oxygen bond leading to fragmentation products. This flow is driven by the continued input of supercritical CO2 and reactants at the start of the process.

The mixture is then delivered to a supercritical chromatography and/or fractionation system which separates out the product, recycles useful reactants and wastes unwanted products.

Advantageously, this third embodiment allows the controlled dilution of the reactants at pressures and temperatures that allow the reaction to proceed. Thus rates of conversion and the exothermic nature of the reaction can be controlled. This is a continuous system that does not waste catalysts and allows a high through-put and reduced costs compared to prior art. Finally, due to the use of chromatography and/or fractionation, recycling of useful reactants and the collection of a purified product can occur. This can all be under the control of feedback from UV, IR, MS, PAS or ARS.

Brief description of drawings

Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which like components are assigned like numerals, and in which: Figure I is a schematic diagram of a system for manufacturing and purifying sevoflurane from chlorosevoether (chloromethyl 2,2,2-trifluoro-I -(trifluoromethyl)ethyl ether dissolved in supercritical CO2 reacted with a sterically-hindered tertiary amine hydrofluoride; Figure 2 is a schematic diagram of a system for the manufacture and purification of sevoflurane from hexaflouroisopropanol (HFIP) with equimolar or excess molar concentrations of paraldehyde or trioxane in the presence of aluminium trichloride to form sevochlorane with subsequent fluoro-substitution by potassium fluoride; Figure 3 is a schematic diagram of a system for the manufacture and purification of desflurane from isoflurane and anhydrous hydrogen fluoride or alkali metal fluoride using a suitable catalyst; Figure 4 is a schematic diagram of a system for the separation of the anaesthetic agent product, desirable reactants and unwanted waste using supercritical chromatography; and Figure 5 is a schematic diagram of a system for the separation and/or condensation of the anaesthetic agent product, desirable reactants for re-use and unwanted waste using fractionation driven by the depressurisation of CO2.

The example embodiments are described in sufficient detail to enable those of ordinary skill in the art to embody and implement the systems and processes herein described. It is important to understand that embodiments can be provided in many alternate forms and should not be construed as limited to the examples set forth herein.

Accordingly, while embodiment can be modified in various ways and take on various alternative forms, specific embodiments thereof are shown in the drawings and described in detail below as examples. There is no intent to limit to the particular forms disclosed. On the contrary, all modifications, equivalents, and alternatives falling within the scope of the appended claims should be included. Elements of the example embodiments are consistently denoted by the same reference numerals throughout the drawings and detailed description where appropriate.

Unless otherwise defined, all terms (including technical and scientific terms) used herein are to be interpreted as is customary in the art. It will be further understood that terms in common usage should also be interpreted as is customary in the relevant art and not in an idealized or overly formal sense unless expressly so defined herein.

All orientational terms are used in relation to the drawings and should not be interpreted as limiting on the invention.

Detailed description of drawings

System 100 for the manufacture of sevoflurane from chlorosevoether is shown in figure I. Carbon dioxide 201 contained in a cylinder 202 passes through a pump 206 to increase the pressure above the critical pressure of CO2 (72.9 bar). The fluid enters an accumulator 208 in a temperature-controlled environment (not shown) above the critical temperature of CO2 (31.1 degrees Centigrade). The supercritical CO2 leaves the accumulator 208 via egress conduit 209 into the reaction chamber 210 made of a pressure and temperature tolerant material, preferably although not exclusively stainless steel or aluminium, and coated in an inert material, preferably but not limited to Teflon or another material that does not react with fluoroethers or supercritical carbon dioxide. Chlorosevoether 211 contained in an inert vessel 2I2a is injected into the reaction vessel 201 by a high pressure injector 207a under the signal 214 of a controller 213. This controller is influenced by the output 215 of a detector 216, preferably UV, MS, PAS or ARS but most favourably IR spectroscopy. Further reagent, in the form of a tertiary amine hydrofluoride salt 217 contained in an inert container 212b is injected into the reaction vessel 210 by a high-pressure injector 207b under the influence of the controller 213 (not shown). The reaction proceeds inside the reaction vessel at temperatures above the critical temperature of carbon dioxide (31.Idegrees Centigrade) and at pressures above the critical pressure of carbon dioxide (72.9bar). Products and reactants proceed through the chamber under the flow of supercritical CO2 from the pump 206 and accumulator 208. This delivers the supercritical solution 218 to the detector 216 to regulate the input of reagent and reaction conditions. The reaction temperature can be altered by changing the temperature of the environment, although it must remain above the critical temperature of CO2. The pressure of the reaction can be altered by the controller influencing the pump 206. The supercritical solution 218 is delivered to chromatography and/or fractional separation modules as shown in figure, for example as shown in Figures 4 and 5.

The system 200 shows the process of manufacture of sevoflurane from hexafluoroisopropanol (HFIP) in figure 2. Carbon dioxide 201 contained in a pressurised cylinder 202 is transferred above critical pressure (72.9 bar) by a pump 206 and passed into an accumulator 208 in a temperature controlled environment (not shown) above the critical temperature of carbon dioxide (31.1 degrees Centigrade). Supercritical CO2 passes into a first reaction chamber 2I0a made of a pressure and temperature tolerant material, preferably although not exclusively stainless steel or aluminium, and coated in an inert material, preferably but not limited to Teflon or another material that does not react with fluoroethers or supercritical carbon dioxide. HFIP 219 in an inert container 212a is fed into the reaction chamber by a high-pressure injector 207a under the signal 214a from a controller 213. Formaldehyde, preferably paraformaldehyde or trioxane 220 contained in an inert container 2I2b, in equimolar or molar excess quantities are also fed into the first reaction chamber 2I0a by injector 207b. The supercritical solution 218 passes from the reaction chamber via a detection device 216a preferably UV, MS, PAS or ARS but most favourably IR spectroscopy into a second reaction chamber 210b containing aluminium trichloride to produce sevochlorane dissolved in supercritical CO2. The products pass through a second detector 2I6b into a third reaction chamber 210c in which potassium fluoride 222 contained in an inert container 212c and dissolved in water is fed into the chamber by injector 207c. Water will quench the reaction of any remaining aluminium hyroxydichloride with sevochlorane. Alternatively solid potassium fluoride could be present inside the third reaction vessel 2I0c. Sevochlorane reacts with the fluorine-donor to produce sevoflurane. Products leave the third reaction chamber to further supercritical chromatography or fractionation for example as shown in figures 4 and 5.

The system 300 shown in figure 3 shows a method for the manufacture of desflurane from isoflurane and a fluorine donor, preferably potassium fluoride, sodium fluoride or anhydrous fluorine. Carbon dioxide 201 contained in a pressurised cylinder 202 is transferred above critical pressure (72.9 bar) by a pump 206 and passed into an accumulator 208 in a temperature controlled environment (not shown) above the critical temperature of carbon dioxide (31.1 degrees Centigrade). Supercritical CO2 passes into a first reaction chamber 2I0a made of a pressure and temperature tolerant material, preferably although not exclusively stainless steel or aluminium, and coated in an inert material, preferably but not limited to Teflon or another material that does not react with fluoroethers or supercritical carbon dioxide.

lsoflurane 224 contained in an inert container 212a is injected into the reaction vessel by high-pressure injector 207a, dissolving into the supercritical CO2. A fluorine donor 223, preferably hydrogen fluoride, potassium fluoride, sodium fluoride or anhydrous fluorine, contained in an inert container 2 I 2b is injected into the reaction chamber 210a by a high-pressure injector 207b. The fluoro-transfer reaction may proceed without catalysis, but may require transfer of the reactants into a second reaction chamber 2I0b, containing a catalyst 225, preferably but not limited to antimony pentahalide, a transition metal trifluoride (for example cobalt trifluoride), transition metal oxide (such as chromia) or mixed with a phase transfer catalyst such as tetramethylammonium chloride. Products including desflurane pass through a detection device 216 preferably UV, MS, PAS or ARS but most favourably IR spectroscopy that relays 215 to a controller 213 to signal 214 and regulate the pump 206 pressures (not shown), the temperature (not shown) and the injectors 207a (not shown) and 207b to control the flow of reactants and solvent into the reaction vessel 2I0a. The products then pass into the supercritical chromatography and/or fractionation systems for example as shown in figures 4 and 5.

Figure 4 shows an agent collection system 600 in which one or more substances are separated from a supercritical solution comprising halocarbon and supercritical fluid. In the presently described embodiment, the supercritical solution is agent-product 230 from which one or more halocarbons are separated. Agent-product 230 is supplied to a chromatography column ingress pipe 602. The agent-product 230 contains three anaesthetic agents 12: agent A 12a; agent B 12b; and agent C I 2c. The agents I 2a, I 2b 12c are dissolved in supercritical CO2. Example agents include isoflurane, sevoflurane and desflurane.

The chromatography column ingress pipe 602 supplies agent-product 230 to a chromatography column 210. A chromatography column egress pipe 604 directs the product of the chromatography column 210 to a back-pressure regulator 205 to which a directional valve 605 is connected. The back-pressure regulator 205 depressurises the product of the chromatography column 210, which causes the product of the chromatography column 210 to cool. To mitigate the effects of cooling, the back-pressure regulator 205 contains a heating module (not shown) that prevents icing following decompression which may lead to sticking of the valve 605. The directional valve 605 is controlled by a controller 607. A FT-IR device 160 monitors the product produced by the chromatography column 210 by firing light through an in-line IR flow cell (not shown) located in the chromatography column egress pipe 604, and sends corresponding signals 614 to the controller 607, which is described further below.

The agent collection system 600 comprises a collection module 608, the interior of which is cooled by a temperature control system to liquefy the anaesthetic agent 12. The interior of the collection module 608 comprises three accumulators: a first heat accumulator 610a, a second heat accumulator 6106 and a third heat accumulator 6I0c.

Each heat accumulator 610a, 610b, 610c is connected to the directional valve 605 by a respective accumulator ingress pipe 612a, 6126, 612c.

The FT-IR device 160 ensures that each heat accumulator 610a, 610b, 610c collects a different agent. For example, when the FT-IR device 160 detects that agent A I 2a is being produced by the chromatography column 210, the FT-IR device 160 sends a signal 614 to the controller 607 which in turn sets the valve 605 so that agent A I 2a flows into the first accumulator 610a. If the FT-IR device 160 detects that that agent B I 2b is being produced by the chromatography column 210, the FT-IR device 160 sends a signal 614 to the controller 607 which in turn sets the valve 605 so that agent B 12b flows into in the second accumulator 610b. Similarly, if the FT-IR device 160 detects that that agent C I 2c is being produced by the chromatography column 210, the FT-IR device 160 sends a signal 614 to the controller 607 which in turn sets the valve 605 so that agent C 12c flows into the third accumulator 610c. Each heat accumulator 6I0a, 6I0b, 6I0c is arranged to transfer heat away from the anaesthetic agent gas I 2a, 12b, 12c which are cooled and liquefy entering it which collects in an associated cyclonic collector 616a, 6166, 616c.

Gaseous CO2 is allowed to escape from each cyclonic collector 616a, 616b, 616c though an associated cyclonic vent 618a, 6186, 618c.

Alternative embodiments may contain further chromatography columns.

Chromatography columns may separate based on polarity, molecular size or weight. The preferred embodiment of the invention uses a size exclusion chromatography column with a pore size that differentiates between the different anaesthetic agents. Alternatively, supercritical fractionation can be used to separate individual anaesthetic agents. This process refers to use of staged depressurisation of CO2 and its use as a driving gas in cold fractionating columns to elute the different agents based on their volatility. Thus lower volatility fractions condense first during slow transit through the column. The more volatile fraction continues into the next column with CO2. In this column, further cooling of the column causes condensation of this fraction and its separation from CO2.

Figure 5 shows an alternative agent collection system 600a which uses fractionation to separate anaesthetic agent 12 from agent-product 230. As above, the agent-product 230 is in a supercritical state when it enters the system 600a. The agent-product 230 flows along a pipe 650 to a back pressure regulator 205. Agent-product 230 is depressurised below critical pressure and warmed to prevent icing by the back pressure regulator 205. Agent-product 230 flows to a first fractionating column 652a along a first fractionating column ingress pipe 654a.

A first fractionating column egress pipe 656a extends from the first fractionating column 652a to a first pressure reducing valve 205a. Pressure is further controlled by the downstream pressure-regulator valve 658a. A second fractionating column ingress pipe 654b extends from the first pressure reducing valve 658a to a second fractionating column 652b. A second fractionating column egress pipe 6566 extends from the second fractionating column 6526 to a second pressure reducing valve 205b.

A vent pipe 659 extends from the second pressure reducing valve 205b to a vent 660.

Each fractionating column 652a, 652b comprises non-absorbent beads 661 a, 661 b, and a cooling jacket 662a, 662b to allow temperature control of each fractionating column 652a, 652b. A first collection vessel 664a is associated with the first fractionating column 652a, and a second collection vessel 664b is associated with the second fractionating column 652b.

The pressure of the solution 503 is lowered in stages by the pressure regulating valves 205a and 205b. Less volatile agent 12, for example Agent X I 2x, is liquefied by the first fractionating column 652a and collects in the first collection vessel 664a. CO2 and anaesthetic agent with a higher volatility, for example Agent Y 12y, passes into the second fractionating column 652b, which may be further depressurised by the pressure regulating valve 205b. Due to the low temperatures in the fractionating column 661 b, the remaining anaesthetic agent liquefies and collects in the second collection vessel.

Gaseous CO2 is released via the vent 660. Alternatively, gaseous CO2 may be recompressed for future use (not shown).

A plurality of fractionating columns may be arranged in parallel which would enable selected agents to be recovered at a higher rate. Alternatively, a plurality of fractionating columns may be arranged in series, as shown in Figure 8, to allow a greater range of agents to be collected.

In alternative embodiments of the invention, in-line infra-red, preferably FT-IR sensor, devices may be used to detect the presence of anaesthetic agents and contaminants in liquidised agent I 2x, 12y. Further separation steps, for example using chromatography or fractional distillation may then be used to achieve the required purity of agent 12x, 12y.

Claims (22)

1. CLAIMSI. A method for the manufacture of desflurane, comprising the steps of: providing isoflurane dissolved supercritical CO2 reacting said isoflurane dissolved supercritical CO2 with a fluorine donor at temperatures at or above the critical temperature of CO2 and pressures at or above the critical pressure of CO2.
2. 2. A method as claimed in claim I, in which the fluorine donor comprises potassium fluoride, sodium fluoride. anhydrous fluorine, or gaseous fluorine.
3. 3. A method as claimed in claim I or claim 2, in which the reaction mixture is passed through a reaction chamber containing a catalyst.
4. 4. A method as claimed in claim 3, in which the catalyst is one or more of an antimony pentahalide, a transition metal trifluoride, a transition metal oxide or a phase transfer catalyst
5. 5. A method as claimed in claim 4, in which the transition metal trifluoride is cobalt trifluoride.
6. 6. A method as claimed in claim 4 or claim 5, in which transition metal oxide is chromia.
7. 7. A method as claimed in any of claims 4 to 6, in which phase transfer catalyst is tetramethylammonium chloride.
8. 8. A method as claimed in any preceding claim, comprising the step of removing unwanted products using chromatography and/or fractional separation.
9. 9. A method as claimed in any preceding claim, comprising the step of selectively capturing wanted products and/or reactants using chromatography and/or fractional separation.
10. 10. A method as claimed in any preceding claim, further comprising the step of collection of a purified product.I.
11. A method as claimed in any preceding claim and being under the control of feedback from a detector.
12. 12. A method as claimed in claim 11 and being under the control of feedback from UV, IR, MS, PAS or ARS.
13. 13. A system for the manufacture and purification of desflurane from isoflurane and a fluorine donor, in which supercritical carbon dioxide passes into a reaction chamber, in which isoflurane is introduced into the reaction chamber, dissolving into the supercritical carbon dioxide, and in which a fluorine donor is introduced into the reaction chamber, thereby causing a fluoro-substitution reaction to form desflurane.
14. 14. A system as claimed in claim 13, in which the reaction proceeds without catalysis.
15. 15. A system as claimed in claim 13, including the presence of a catalyst.
16. 16. A system as claimed in claim 15, further comprising the transfer of the reactants into a second reaction chamber containing a catalyst.
17. 17. A system as claimed in any of claims 13 to 16, in which products including desflurane pass through a detection device so as to allow control the flow of reactants and solvent into the reaction vessel.
18. I 8. A system as claimed in any of claims 13 to 17, in which products pass into a supercritical chromatography and/or fractionation system.
19. 19. A method for synthesis of desflurane by the fluoro-substitution of isoflurane.
20. 20. A system for the manufacture and purification of desflurane from isoflurane and anhydrous hydrogen fluoride or alkali metal fluoride using a suitable catalyst.
21. 21. A system as claimed in claim 20, including means for the separation of the anaesthetic agent product, desirable reactants and unwanted waste using supercritical chromatography.
22. 22. A process for the preparation of desflurane, in which isoflurane is dissolved and diluted in supercritical CO2 at supercritical temperatures and pressures, and in which potassium fluoride, sodium fluoride or anhydrous fluorine are added to the mixture at concentrations that control the exothermic nature of a fluoro-substitution reaction forming desflurane.