Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1998-06-30
1999-11-23
Shippen, Michael L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C07C 4100
Patent
active
059903597
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the production of fluoromethylhexafluoroisopropylether of formula CH.sub.2 F.CH(CF.sub.3).sub.2 which is the anaesthetic "Sevoflurane".
Several processes have been proposed for the production of Sevoflurane including the reaction of hexafluoroisopropyl alcohol, (CF.sub.3).sub.2 CHOH, with formaldehyde and hydrogen fluoride. One such process comprising adding hexafluoroisopropyl alcohol to a mixture of paraformaldehyde and hydrogen fluoride plus sufficient sulphuric acid to sequester most of the water formed at a temperature above 57.degree. C. is described in U.S. Pat. No. 4,250,334. A similar process comprising mixing hexafluoroisopropyl alcohol, formaldehyde, hydrogen fluoride and a dehydrating agent such as sulphuric acid is described in U.S. Pat. No. 4,469,898.
A process for producing an alpha-fluoroether such as and including Sevoflurane is described in International Patent Publication No WO 93/12057, the process comprising reacting a non-enolisable aldehyde such as formaldehyde with hydrogen fluoride to form an intermediate and reacting the intermediate with an alcohol such as hexafluoroisopropyl alcohol to form an alpha-fluoroether such as Sevofluorane. The production of Sevoflurane by adding hexafluoroisopropyl alcohol to the reaction mixture derived from trioxane (as the source of formaldehyde) and hydrogen fluoride and containing the intermediate bis(fluoromethyl)ether is described in Example 19.
As is described in WO 93/12057, the reaction products obtained in Example 19 comprised mainly unreacted hexafluoroisopropyl alcohol (72% by mass spectroscopic analysis) and unreacted bis(fluoromethyl)ether (22%) and the yield of Sevoflurane was only 4.9%. This very low yield of Sevoflurane renders the process unsuitable or at best barely suitable for industrial application even with recovery anti recycle of unreacted hexafluoroisopropyl alcohol and bis(fluoromethyl)ether.
The present invention is based on the discovery that separation of the intermediate bis(fluoromethyl)ether from the reaction mixture before addition of the hexafluoroisopropyl alcohol results in a process in which Sevoflurane is obtained in high yield and in particular can be obtained as the major product of the reaction.
According to the present invention there is provided a process for the production of fluoromethylhexafluoroisopropylether [Sevoflurane] which comprises reacting essentially pure bis(fluoromethyl) ether with hexafluoroisopropyl alcohol and recovering the resulting fluoromethylhexafluoroisopropylether from the reaction products.
The bis(fluoromethyl)ether is conveniently and preferably produced by the reaction of formaldehyde or a source of formaldehyde with hydrogen fluoride and according to a particular embodiment of the invention there is provided a process for the production of fluoromethylhexafluoroisopropylether which comprises reacting formaldehyde with hydrogen fluoride to produce a reaction mixture containing bis(fluoromethyl)ether, separating essentially pure bis(fluoromethyl)ether from the reaction mixture, reacting the resulting essentially pure bis(fluoromethyl)ether with hexafluoroisopropyl alcohol and recovering the resulting fluoromethylhexafluoroisopropylether from the reaction products.
The reaction between the bis(fluoromethyl)ether and the hexafluoroisopropyl alcohol is conveniently carried out at ambient temperature, say 20.degree. C. to 30.degree. C. and at atmospheric pressure, although if desired subatmospheric or superatmospheric pressure and a range of temperatures from about 0.degree. C. to about 100.degree. C. may be employed. The reaction is preferably carried out in the presence of an acid such as sulphuric acid. A slight exotherm resulting in a rise in temperature of the reaction mixture may be observed but in general there is no real advantage in applying heat to the reaction mixture.
The reaction can be readily carried out to result in complete conversion of the hexafluoroisopropyl alcohol and with an acceptable selectivity to the desired Sevofluran
REFERENCES:
patent: 5750807 (1998-05-01), Burgess
Burgess Leslie
Ryan Thomas Anthony
Imperial Chemical Industries plc
Shippen Michael L.
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