Synthesis of fluorinated ethers

Details Synthesis of fluorinated ethers Synthesis of fluorinated ethers

2000-03-14

2001-05-01

Oswecki, Jane C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

Reexamination Certificate

active

06225511

ABSTRACT:

This invention relates to the preparation of fluorinated ethers, and, especially, 2-difluoromethoxy-1,1,1,2-tetrafluoroethane, of formula: CF
3
CHFOCHF
2
.
This compound, called Desflurane, is known to have valuable anaesthetic properties—see, for example, E. I. Eger et al, Anaesthesia and Analgesia 1987, Volume 66 (10), pp. 971-973, 974-976, 977-982, 983-985, 1227-1229, 1230-1233, and 1312-1315.
This compound is mentioned in U.S. Pat. No. 3,897,502 (Example XXI; column 8, Table 1) and at column 1, line 23 ff, where it is stated that “polyfluoro containing products which can be made by the method of this invention are also useful as agents for producing anaesthesia in anaesthetic-susceptible, air breathing mammals”.
The process disclosed in U.S. Pat. No. 3,897,502 for the production of this compound involves the direct fluorination of 2-difluoromethoxy-1,1,1-trifluoroethane. The reaction, which took 13 hours to complete, was conducted in the solvent Freon E3, using a mixture of 20% fluorine gas in argon, at −20° to −25° C. to control the exothermic process.
This process is obviously difficult to develop to a commercial scale, since expensive reagents are used, and the reaction has to be carried out at low temperature and is slow. Further, it is known to those skilled in the art that the interaction of fluorine gas and partially fluorinated hydrocarbon compounds is liable to cause explosions.
Other published routes to 2-difluoromethoxy-1,1,1,2-tetrafluoroethane involve
(a) reaction of CHCl
2
OCH
2
COCl or CHCl
2
OCHClCOCl (or a mixture of the two) with sulphur tetrafluoride (U.S. Pat. No. 4,855,511). This is a multistage process, using the highly toxic gaseous reagent sulphur tetrafluoride, which must be handled under pressure. There are likely to be significant handling problems on scale-up.
(b) reaction of CF
3
CHClOCF
2
H with potassium fluoride. This can be carried out in the absence of solvent at 278° C. under a pressure of 500 p.s.i. (3450 kPa) in an autoclave, (U.S. Pat. No. 4,874,901) or in the presence of an aprotic solvent (sulpholane) with a phase transfer catalyst (tetramethyl ammonium chloride) at 210° C., again under pressure (UK Patent Specification No. 2,219,292). Since these processes have to be operated under pressure, they suffer from the disadvantage of high capital cost, and problems in scale-up—especially from the corrosive nature of the reagents. They are essentially batch processes.
(c) reaction of CF
3
CHClOCF
2
H with bromine trifluoride at ambient temperature (European Patent Specification No. 341,004). Although this process gives a good yield (87%) in a short time, the reagent, bromine trifluoride, which is prepared from bromine and fluorine, is highly toxic and difficult to handle, leading to problems in scale-up to commercial quantities.
Accordingly, there is need for a process which can be used on an industrial scale without significant problems. It has now been found that certain fluorinated aliphatic ethers, including Desflurane, can be produced from corresponding less fluorinated ethers by contacting the latter in the vapour phase with a solid transition metal fluoride fluorinating agent.
The present invention accordingly provides a process for the preparation of a fluorinated ether of the formula
wherein R is hydrogen, fluorine, alkyl of 1 to 6 carbon atoms or fluoroalkyl of 1 to 6 carbon atoms, R′ is hydrogen, alkyl of 1 to 6 carbon atoms, or fluoroalkyl of 1 to 6 carbon atoms, and R″ is fluorine, alkyl of 1 to 6 carbon atoms or fluoroalkyl of 1 to 6 carbon atoms, which comprises reacting an ether of the formula:
where R, R′ and R″ are as hereinbefore defined in the vapour phase with a solid transition metal fluoride fluorinating agent. The aforesaid fluoroalkyl groups are preferably perfluoroalkyl groups.
In the preferred operation of the process R is hydrogen or fluorine, especially hydrogen, R′ is hydrogen or 1,2,2,2-tetrafluoroethyl, especially hydrogen and R″ is fluorine.
Using the new process, the relatively easily available compound 2-difluoromethoxy-1,1,1-trifluoroethane (CF
3
CH
2
OCHF
2
) can be fluorinated under relatively mild conditions in the vapour phase to 2-difluoromethoxy-1,1,1,2-tetrafluoroethane, i.e. Desflurane, using preferably cobalt trifluoride as the fluorinating agent. Difluoromethoxy-1,1,1,2,2-pentafluoro-ethane is produced at the same time.
Although cobalt trifluoride (cobaltic fluoride) is the preferred fluorinating reagent, other transition metal fluorides, which may be in the form of their alkali metal complexes, effective in replacing a hydrogen atom attached to carbon by fluorine may be used, e.g. silver difluoride, potassium tetrafluorocobaltate (KCoF
4
), potassium hexafluoronickelate (K
2
NiF
6
), manganese trifluoride, cerium tetrafluoride, mercuric fluoride and potassium tetrafluoroargentate (KAgF
4
). For simplicity the following discussion refers to cobalt trifluoride which is preferred.
Advantageously, in the operation of the new process, the transition metal fluoride fluorinating agent can be regenerated in situ during the reaction by passing fluorine into the reaction zone so that the cobalt trifluoride acts as a fluorine carrier. The following reactions, for example, then take place simultaneously:
CF
3
CH
2
OCHF
2
+2CoF
3
→CF
3
CHFOCHF
2
+2CoF
2
+HF
2CoF
2
+F
2
→2CoF
3
A cobalt trifluoride-based process is used commercially for the production of saturated fluorocarbons as described in, e.g., Preparation, Properties, and Industrial Applications of Organofluorine Compounds ed. R E Banks, published by Ellis Horwood/Wiley, 1982, p, 47) and the apparatus described therein may easily be used for the process of the present invention. The process of the present invention therefore provides a safe and economic route to 2-difluoromethoxy-1,1,1,2-tetrafluoroethane, which can easily be developed to commercial scale.
Since the trifluoroethane starting material has a boiling point of 29.2° C., simple heating will vaporise it. The fluorination will, in general, be carried out by contacting the ether starting material with cobalt trifluoride at a temperature of 100° to 450° C., preferably 150° C. to 300° C. and especially about 220° C. at atmospheric pressure. The cobalt trifluoride will normally be in a significant excess. This can be achieved quite simply by passing the ether starting material as a vapour through a bed of cobalt trifluoride, generally agitated, for example by stirring.
In one preferred embodiment of the invention, the starting material and the fluorine are continuously introduced into the reaction vessel, and the respective rates of introduction of these reagents are controlled so that the proportion of the cobalt (or other metal) in the form of the active fluorinating agent (e.g. CoF
3
) is from 10% to 100% of the total cobalt or other metal, usually 10% to 80% and especially 33 to 67%.
While the starting material is preferably introduced as a vapour it can also be introduced in liquid form. If desired it may be mixed with a carrier gas, e.g. to facilitate temperature control, but this can reduce productivity.
The 2-difluoromethoxy-1,1,1-trifluoroethane starting material for the production of Desflurane can be obtained by known methods, for example by reacting trifluoroethanol with monochlorodifluoromethane under alkaline conditions (see, for example, UK Patent No. 1358960).
Purification of the crude product to the required quality can be achieved by the usual techniques of fractional distillation, using a column equipped with a high efficiency packing. Desflurane of high purity (>99.97%) can be obtained by a simple distillation. The level of impurities (other than unchanged starting material) is less than 30 ppm each.


REFERENCES:
patent: 2614129 (1952-11-01), McBee et al.
patent: 3897502 (1975-07-01), Russell et al.
patent: 0 341 005 (1989-11-01), None
patent: WO 84/02909 (1984-07-01), None

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