CA2241630C - Process for the production of fluoromethylhexafluoroisopropylether - Google Patents
Process for the production of fluoromethylhexafluoroisopropylether Download PDFInfo
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- CA2241630C CA2241630C CA002241630A CA2241630A CA2241630C CA 2241630 C CA2241630 C CA 2241630C CA 002241630 A CA002241630 A CA 002241630A CA 2241630 A CA2241630 A CA 2241630A CA 2241630 C CA2241630 C CA 2241630C
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- ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/14—Preparation of ethers by exchange of organic parts on the ether-oxygen for other organic parts, e.g. by trans-etherification
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Abstract
Process for producing Sevoflurane anaesthetic which comprises reacting hexafluoroisopropyl alcohol with essentially pure bis(fluoromethyl)ether. The bis(fluoromethyl)ether is preferably obtained by the reaction of formaldehyde with hydrogen fluoride.
Description
PRO ,~S_ FOR THE PRODUCTION OF
F1~UOROM~THYLH~A~LtTOROISOPROPYLETHER.
This invention relates to a process for the production of fluoromethylhacatluoroisopropylether offormula CHzFOCFi(CF,), which is the S anaesthetic "Sevo~urane".
Several processes have been proposed for the production of Sevo$urane including the rearxioa of hexafluoroisopropyl alcohol, (CF~CHOH, with formaldehyde and hydrogen fluoride. One such process comprising adding haca$uoroisopmpyl alcohol to a mi~ue of paraformalddiyde and hydrogen $uoride plus sufficient sulphuric and to 10 sequester most of the water formed at a temperature above S7°C is described in US
4,250,334. A similar process compt'ismg mixing hexafluoroisopropyI alcohol, formaldehyde, hydrogen $uoride and a dehydrating agent such as sulphuric acid is described in US 4,469,898.
A process for producing an alpha-$uoroether such as and including Sevoflurane is I S described in International Patent Publication No WO 93//20S7, the process comprising reacting a non-enolisable aldehyde such as formalddryde with hydrogen fluoride to form an intermediate and ring the iute:mediste with an alcohol such as heacafluoroisopropyi alcohol to form an alpha-auoroether such as Sevofluorane.
The production of Sevoflurane by adding hrxafluoroisopmpyl alcohol to the reaction 20 mixture derived from trioxane (as the source of formaldehyde) and hydrogen fluoride and containing the intermediate bis(fluoromethyl~ther is described in Example 19.
As is descnbed in WO 93/12057, the reaction products obtained in Example 19 comprised mainly unreacted hexafluoroisopropyl alcohol (72% by mass spectroscopic analysis) and um~acted bis($uoromethyl)ether (22%) and the yidd of Sevoflurane was 2S only 4.9%. This very low yidd of Sevo$urane renders the process unsuitable or at best hardy suitable for industrial application even with recovery and recycle of unreacted hexafluoroisoproPyl alcohol and bis(fluommcthyl)ether.
The present invention is based on the discovery that separation of the intermediate bis(fluoromethyI~ther from the reaction mixture before addition of the 30 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.
WO 97/25303 PCTlGB96/03001 According to the present invention there is provided a process for the production of fluoromethylhexafluoroisopropylether [Sevofluranej 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.
I S The reaction between the bis(fluoromethyl)ether and the hexafluoroisopropyl alcohol is conveniently carried out at ambient temperature, say 20°C to 30°C and at atmospheric pressure, although if desired subatmospheric or superatmospheric pressure and a range of temperatures from about 0°C to about 100°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 Sevoflurane product although a significant amount, say 20% or more, of the acetal (CF3)ZCHOCHa OCH2F is usually produced as a by-product. It is a matter of mere routine experimentation to optimise the reaction conditions to maximise the yield of Sevoflurane and minimise the yield ofby-products such as the acetal. A
reaction product mixture in which Sevoflurane is the major component with a yield of at least about 55% and preferably about 60% or more is obtained. Carrying out the reaction with complete conversion of the hexafluoroisopropyl alcohol obviates the need to recover and recycle unreacted alcohol.
F1~UOROM~THYLH~A~LtTOROISOPROPYLETHER.
This invention relates to a process for the production of fluoromethylhacatluoroisopropylether offormula CHzFOCFi(CF,), which is the S anaesthetic "Sevo~urane".
Several processes have been proposed for the production of Sevo$urane including the rearxioa of hexafluoroisopropyl alcohol, (CF~CHOH, with formaldehyde and hydrogen fluoride. One such process comprising adding haca$uoroisopmpyl alcohol to a mi~ue of paraformalddiyde and hydrogen $uoride plus sufficient sulphuric and to 10 sequester most of the water formed at a temperature above S7°C is described in US
4,250,334. A similar process compt'ismg mixing hexafluoroisopropyI alcohol, formaldehyde, hydrogen $uoride and a dehydrating agent such as sulphuric acid is described in US 4,469,898.
A process for producing an alpha-$uoroether such as and including Sevoflurane is I S described in International Patent Publication No WO 93//20S7, the process comprising reacting a non-enolisable aldehyde such as formalddryde with hydrogen fluoride to form an intermediate and ring the iute:mediste with an alcohol such as heacafluoroisopropyi alcohol to form an alpha-auoroether such as Sevofluorane.
The production of Sevoflurane by adding hrxafluoroisopmpyl alcohol to the reaction 20 mixture derived from trioxane (as the source of formaldehyde) and hydrogen fluoride and containing the intermediate bis(fluoromethyl~ther is described in Example 19.
As is descnbed in WO 93/12057, the reaction products obtained in Example 19 comprised mainly unreacted hexafluoroisopropyl alcohol (72% by mass spectroscopic analysis) and um~acted bis($uoromethyl)ether (22%) and the yidd of Sevoflurane was 2S only 4.9%. This very low yidd of Sevo$urane renders the process unsuitable or at best hardy suitable for industrial application even with recovery and recycle of unreacted hexafluoroisoproPyl alcohol and bis(fluommcthyl)ether.
The present invention is based on the discovery that separation of the intermediate bis(fluoromethyI~ther from the reaction mixture before addition of the 30 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.
WO 97/25303 PCTlGB96/03001 According to the present invention there is provided a process for the production of fluoromethylhexafluoroisopropylether [Sevofluranej 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.
I S The reaction between the bis(fluoromethyl)ether and the hexafluoroisopropyl alcohol is conveniently carried out at ambient temperature, say 20°C to 30°C and at atmospheric pressure, although if desired subatmospheric or superatmospheric pressure and a range of temperatures from about 0°C to about 100°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 Sevoflurane product although a significant amount, say 20% or more, of the acetal (CF3)ZCHOCHa OCH2F is usually produced as a by-product. It is a matter of mere routine experimentation to optimise the reaction conditions to maximise the yield of Sevoflurane and minimise the yield ofby-products such as the acetal. A
reaction product mixture in which Sevoflurane is the major component with a yield of at least about 55% and preferably about 60% or more is obtained. Carrying out the reaction with complete conversion of the hexafluoroisopropyl alcohol obviates the need to recover and recycle unreacted alcohol.
2 The amounts of bis(fluoromethyl)ether and hexafluoroisopropyl alcohol will usually be such that the molar ratio of the ether to the alcohol is from about 0.5 : 1 to about 1.5 : 1. In general about equimolar amourns of ether and alcohol or as excess of the ether will be used to ensure complete conversion of the alcohol. However, it has been observed that a large excess of the ether is undesirable in chat it tends to result in the formation of a preapitate of granular cx~ystais (poss~ly due to polymerisation of products of decomposition of the ether) and we prefer to employ a mole ratio of ether to alcohol of no greater than about 2 : 1.
The separation, recovery and purification of Sevoflutane from product streams comaining it is known and any of the known methods may be used in the process of the invention. Such methods will usually include at least one distillation step and will usually include a step of separating and recovering arty bis(fluoromethyl)ether present in the product stream.The ether recovered from the product stream can be recycled to the reaction with hexafluoroisopropyl alcohol The process can be operated as a batch or continuous process or a combination thereof but is preferably operated as a continuous process with recycle of recovered bis(fluoromethyl~her.
As stated herinbefore, a prtfeted embodiment of the imrention includes the step of producing the bis(fluoromethyl)ether by reaction of formaldehyde (or a polymeric form of formaldehyde such as paraformaldehyde or trioxane) with hydrogen fluoride.
Any of the known methods for production of the bis(fluoromethyl)ether may be employed as the ether formation step of this embodiment of the present invention. The production of bis(fluoromethyl~ther from formaldehyde and hydrogen fluoride is described, for atannple, in European Patent Publication No. 518,506 and in International Patent Publications No. WO 93/10070, WO 93/12057 and WO 93/22265.
In the present invention we especially prefer to employ the ether production process described in International Patent Publication No. WO 93/10070 which comprises reacting formaldehyde with hydrogen fluoride in a reaction-distiuation column from which the ether is withdrawn in as~ally pure form and in particular essartialIy free from water.
The invention is illustrated but in no way limited by the following Example.
The separation, recovery and purification of Sevoflutane from product streams comaining it is known and any of the known methods may be used in the process of the invention. Such methods will usually include at least one distillation step and will usually include a step of separating and recovering arty bis(fluoromethyl)ether present in the product stream.The ether recovered from the product stream can be recycled to the reaction with hexafluoroisopropyl alcohol The process can be operated as a batch or continuous process or a combination thereof but is preferably operated as a continuous process with recycle of recovered bis(fluoromethyl~her.
As stated herinbefore, a prtfeted embodiment of the imrention includes the step of producing the bis(fluoromethyl)ether by reaction of formaldehyde (or a polymeric form of formaldehyde such as paraformaldehyde or trioxane) with hydrogen fluoride.
Any of the known methods for production of the bis(fluoromethyl)ether may be employed as the ether formation step of this embodiment of the present invention. The production of bis(fluoromethyl~ther from formaldehyde and hydrogen fluoride is described, for atannple, in European Patent Publication No. 518,506 and in International Patent Publications No. WO 93/10070, WO 93/12057 and WO 93/22265.
In the present invention we especially prefer to employ the ether production process described in International Patent Publication No. WO 93/10070 which comprises reacting formaldehyde with hydrogen fluoride in a reaction-distiuation column from which the ether is withdrawn in as~ally pure form and in particular essartialIy free from water.
The invention is illustrated but in no way limited by the following Example.
3 WO 97!25303 PCT/GB96/03001 Exam lie.
Bis(fluoromethyl)ether (2g) of purity approximately 99% was mixed with stirring into hexafluoroisopropyl alcohol (4. !g) at room temperature (approximately 25°C) and pressure and sulphuric acid ( 1 ml of 98% acid) was added to the mixture. A
slight exotherm was noted. After 10 minutes, the mixture was neutralised by adding sodium hydTOxide and then analysed by gas chromatography/mass spectometry.
The composition of the product mixture determined by GC/MS analysis was:-%age of mixture Sevoflurane 59.7 IO Acetal * 21.6 Bis(fluoromethyl)ether 17.I
Methyl formate 1.6 i5 For purposes of comparison the product mixture obtained in Example 19 of WO
93/I2057 was determined by GC/MS analysis to be:-%age of mixture Sevoflurane 4.9 20 Acetal * 1.3 Bis(fluoromethyl)ether 22.2 Hexafluoroisopropanol 71.6
Bis(fluoromethyl)ether (2g) of purity approximately 99% was mixed with stirring into hexafluoroisopropyl alcohol (4. !g) at room temperature (approximately 25°C) and pressure and sulphuric acid ( 1 ml of 98% acid) was added to the mixture. A
slight exotherm was noted. After 10 minutes, the mixture was neutralised by adding sodium hydTOxide and then analysed by gas chromatography/mass spectometry.
The composition of the product mixture determined by GC/MS analysis was:-%age of mixture Sevoflurane 59.7 IO Acetal * 21.6 Bis(fluoromethyl)ether 17.I
Methyl formate 1.6 i5 For purposes of comparison the product mixture obtained in Example 19 of WO
93/I2057 was determined by GC/MS analysis to be:-%age of mixture Sevoflurane 4.9 20 Acetal * 1.3 Bis(fluoromethyl)ether 22.2 Hexafluoroisopropanol 71.6
4
Claims (5)
1. A process for the production of fluoromethylhexafluoroisopropylether which comprises reacting essentially pure bis(fluoromethyl)ether with hexafluoroisopropyl alcohol and recovering the resulting fluoromethylhexafluoroisopropylether from the reaction products.
2. A process as claimed in claim 1 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 and reacting the essentially pure bis(fluoromethyl)ether with hexafluoroisopropyl alcohol.
3. A process as claimed in claims 1 or 2 in which the essentially pure bis(fluoromethyl)ether is reached with hexafluoroisopropyl alcohol in the presence of an acid.
4. A process as claimed in any one of claims 1 to 3 in which the molar ratio of bis(fluoromethyl)ether to hexafluoroisopropyl alcohol is 0.5:1 to 2:1.
5. A process as claimed in any one of claims 1 to 4 in which the yield of fluoromethylhexafluoroisopropylether is at least about 55%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9600072.4A GB9600072D0 (en) | 1996-01-04 | 1996-01-04 | Process for the production of fluoromethylhexafluoroisopropylether |
| GB9600072.4 | 1996-01-04 | ||
| PCT/GB1996/003001 WO1997025303A1 (en) | 1996-01-04 | 1996-12-06 | Process for the production of fluoromethylhexafluoroisopropylether |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2241630A1 CA2241630A1 (en) | 1997-07-17 |
| CA2241630C true CA2241630C (en) | 2006-10-24 |
Family
ID=37387455
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002241630A Expired - Fee Related CA2241630C (en) | 1996-01-04 | 1996-12-06 | Process for the production of fluoromethylhexafluoroisopropylether |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2241630C (en) |
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1996
- 1996-12-06 CA CA002241630A patent/CA2241630C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CA2241630A1 (en) | 1997-07-17 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |