WO2003064371A1

WO2003064371A1 - Synthesis of fluorinating agents

Info

Publication number: WO2003064371A1
Application number: PCT/GB2003/000420
Authority: WO
Inventors: Mandy Clement
Original assignee: F2 Chemicals Limited
Priority date: 2002-02-01
Filing date: 2003-02-03
Publication date: 2003-08-07
Also published as: GB0202358D0

Abstract

The invention provides a method for the preparation of an acyl hypofluorite (I), the method comprising treating a mixture comprising a lower nitrile and a carboxylic acid with elemental fluorine. The preferred acyl hypofluorite is acetyl hypofluorite, the corresponding carboxylic acid is acetic acid, and the preferred nitrile is acetonitrile. The reaction is preferably carried out in a single phase on a continuous basis at room temperature, by treating a mixture of nitrile and carboxylic acid with a stream containing 10% fluorine gas in an inert gas such as nitrogen.

Description

SYNTHESIS OF FLUORINATING AGENTS

This invention relates to selective fiuorinating agents and novel methods for their preparation. More particularly, it is concerned with the synthesis of electrophilic fiuorinating agents which contain a fluorooxy group bonded to a non-fluorinated alkyl radical, specifically acyl hypofhiorites (I)

R-C0₂F (I)

wherein R is an alkyl group.

The synthesis of acetyl hypofluorite was first reported by Rozen et al (S. Rozen, O. Lerman and M. Kol, J Chem. Soc, Chem. Commun., 1981, 443), and the method required elemental fluorine to be passed through a suspension of acetic acid and either sodium acetate or sodium fluoride in Freon 11 (trichlorofluoromethane) at -78°C. The use of the material as an electrophilic fiuorinating agent has subsequently been the subject of widespread investigation, and it has found particular application in the preparation of ^lsF-labelled organofluorine compounds.

Subsequent work by Jewett and his co-workers (D. M. Jewett, J. F. Potocki and R. E. Ehrenkaufer, Syn. Commun., 1984, 14, 45; Idem., J. Fluorine Chem., 1984, 24, 477) was directed towards the synthesis of acetyl hypofluorite by means of a gas-solid- phase technique which involved passing fluorine gas, diluted with nitrogen, through columns containing complexes of alkali metal acetates, such as potassium acetate, with acetic acid.

Like Rozen and his co-workers, however, Jewett et al did not succeed in isolating a sample of acetyl hypofluorite and it was left to Appelman et al (E. V. Appelman, M. H. Mendelsohn and H. Kim, J. Amer. Chem. Soc, 1985, 107, 6515) to subsequently report the isolation and characterisation of the material, using the gas-solid-phase technique of Jewett and trapping the product at -78°C. Acetyl hypofluorite was found to be a pale yellow liquid with a melting point of around -96°C and a boiling point, extrapolated from vapour pressure measurements, in the region of 53°C. Unfortunately, however, the material has proved to be extremely unstable, with the liquid being much less stable than the vapour and rapid, sometimes explosive, decomposition of the liquid is found to occur unpredictably even at temperatures below -80°C. When using containers comprising Teflon^®, or other similar materials, the decomposition products are methyl fluoride and carbon dioxide, but decomposition occurs more rapidly when the material comes into contact with Monel and, in this case, a significant amount of methyl fluoro formate is formed.

Despite its hazardous nature, acetyl hypofluorite has remained a popular fiuorinating agent, but it applications have been severely limited due to the fact that it has to be used without isolation. The known preparative techniques involve the use of low temperatures and some require cumbersome gas-solid-phase technology to be employed. The original method of Rozen, which does use solvent technology, suffers from the disadvantage that it includes trichlorofluoromethane as a solvent, since this material is known to be a major ozone-depleting agent, and is, therefore, extremely hazardous to the environment.

Rozen has subsequently (S. Rozen, Y. Bareket and M. Kol, J. Fluorine Chem., 1993, 61, 141) devised a preparative method which eliminates the requirement for the use of trichlorofluoromethane. Thus, the hypofluorite may be prepared by passing fluorine gas, diluted by an inert gas, through a suspension of sodium acetate in acetonitrile and acetic acid at -45°C. It was found that the replacement of trichlorofluoromethane with acetonitrile did not impair the efficiency of the reaction. However, like the earlier method, this procedure has the disadvantage that it requires the use of a two-phase system, with the sodium acetate being suspended in the acid/solvent mixture.

Despite the various successes reported in the prior art, it was clear that the preparative methods which were available, and the safety considerations which were associated with the material, rendered its use impractical for other than experimental scale syntheses. It was apparent that the compound had to be prepared at low temperatures and, essentially, via small-scale batchwise procedures; however, commercial usage would require more convenient operating temperatures to be employed and, in view of the impracticality of attempting to isolate the compound, it would only be realistic to consider its use in a continuous flow process. Whilst the method of Jewett et al could be considered to be a continuous process, it would be totally inefficient on a large scale due to the very dilute concentrations of fluorine which are employed.

Further work reported by Rozen (S. Rozen and D. Hebel, J. Org. Chem., 1990, 55, 2621) has indicated the feasibilty of obtaining alternative acyl hypofluorites to acetyl hypofluorite. Specifically, it has been seen that compounds having a synthetically useful lifetime may be prepared when using precursors which comprise alkyl chains having six or less carbon atoms, and/or which include electron withdrawing groups at the 2 -position. However, the preparative techniques employed again required the use of very low temperatures and two-phase reactions in order to obtain useful results.

Consequently, the present invention seeks to provide a method for the synthesis of acetyl hypofluorite, and other acyl hypofluorites, which overcomes the problems associated with the prior art, and allows the commercial, large-scale, use of these materials as fluorination agents. It has, therefore, been the aim of the present inventors to devise a process which can be carried out on a continuous basis, thereby preventing the build-up of significant quantities of the hypofluorite, which does not necessitate the use of very low temperatures, which can be carried out in a single

(solution) phase, and which facilitates chemical manufacture in commercial quantities. Surprisingly, it has now been found the preparation of acyl hypofluorites can be achieved at convenient ' temperatures near to the ambient by the direct fluorination of a mixture comprising a lower nitrile and a carboxylic acid. Thus, according to the present invention, there is provided a method of preparing an acyl hypofluorite (I), the method comprising treating a mixture comprising a lower nitrile and a carboxylic acid with elemental fluorine.

Preferably, the acyl hypofluorite comprises acetyl hypofluorite and the carboxylic acid comprises acetic acid. Alternative carboxylic acids include, in particular, derivatives including Cι_-6 alkyl chains and those which incorporate at least one electron withdrawing substituent, such as a chloro group, at the 2-position; examples include 2,2-dichloropropionic acid and monoethyl malonate. Preferably, the lower nitrile comprises a C_1-6 alkyl nitrile, most preferably acetonitrile.

It is particularly preferred that the reaction mixture comprises a single phase, specifically a single solution phase. Thus the present invention is able to overcome the disadvantages associated with the two-phase systems of the prior art. Furthermore, the use of a single phase system facilitates the ready application of the method of the present invention in continuous manufacturing systems, thereby allowing for much greater commercial flexibility in terms of scale.

The elemental fluorine is preferably in the form of fluorine gas, which is bubbled through a stirred mixture of the nitrile and carboxylic acid. It is preferred that the fluorine is comprised in admixture with an inert gas, most preferably nitrogen. Most successful results are obtained when the fluorine comprises in the range from 2-30% of the mixture with the inert gas, preferably from 5-20%, most preferably 10-15%.

The reaction may be carried out at a temperature around the ambient and, typically, is performed in the range from -20° to +25°C. However, the preferred range, for ease of operation, is from -15° to +5°C, with particularly successful results being achieved around -10°C.

Typically, the mixture of nitrile and carboxylic acid comprises between 5 and 80% v/v of the carboxylic acid, and the remainder nitrile. Particularly favourable results may be obtained at carboxylic acid levels of 5 to 20% v/v, and especially in the region of 10% v/v.

Preferably, the mixture is treated with between 0.5 and 5 molar equivalents of fluorine per mole of carboxylic acid, with the most favourable results being achieved when using approximately equimolar amounts of these reactants.

hi order that the reaction may be performed on a continuous basis, it is most conveniently carried out using a flow reactor, wherein the newly formed acyl hypofluorite may be directly transferred to another reaction vessel wherein it acts as a fiuorinating agent upon a suitable substrate. A typical flow reactor would, for example, comprise separate inlets for the nitrile/carboxylic acid mixture and the elemental fluorine, a reaction zone, and separate outlets - one for collecting the reaction mixture, or directly transferring it to another vessel, and another for venting exhaust gases, or directing them to a scrubber system.

Without limiting the scope of the present invention, an embodiment of the method of the invention will now be illustrated by reference to Figure 1, which shows an apparatus for performing the method, the apparatus comprising a flow reactor 1 which comprises inlet tubes 2 and 3, outlet tubes 4 and 5 and reaction zone 6, this zone being packed with polytetrafluoroethylene (PTFE) material. The apparatus is constructed from PTFE, apart from the gas inlet tube 3 which comprises fluorinated ethylene propylene (FEP), and all sections have internal diameter of 7 mm and external diameter of 10 mm.

hi use, a mixture of nitrile and carboxylic acid is introduced via inlet 2, whilst elemental fluorine, preferably mixed with inert gas, is fed through inlet 3. Following reaction in the reaction zone 6, the reaction mixture, comprising an acyl hypofluorite, is fed to a remote reaction vessel via the outlet 4, whilst the outlet 5 is connected to a scrubber. By this means, 45 mmol of acetyl hypofluorite has been successfully prepared from a starting mixture comprising 90 ml acetonitrile and 10 ml acetic acid.

Claims

1. A method of preparing an acyl hypofluorite (I)

R-CO₂F (I)

wherein R is an alkyl group, the method comprising treating a mixture comprising a lower nitrile and a carboxylic acid with elemental fluorine.

2. A method as claimed in claim 1 wherein the acyl hypofluorite comprises acetyl hypofluorite and the carboxylic acid comprises acetic acid.

3. A method as claimed in claim 1 wherein the carboxylic acid comprises at least one of:

(a) a Cι_-6 alkyl group;

(b) at least one electron withdrawing group at the 2- position.

4. A method as claimed in claim 3 wherein the carboxylic acid comprises 2,2- dichloropropionic acid.

5. A method as claimed in claim 3 wherein the carboxylic acid comprises monoethyl malonate.

6. A method as claimed in any one of claims 1 to 5 wherein the lower nitrile comprises a C_1-6 alkyl nitrile.

7. A method as claimed in claim 6 wherein the Cι_-6 alkyl nitrile comprises acetonitrile.

8. A method as claimed in any preceding claim wherein the reaction mixture comprises a single phase.

9. A method as claimed in claim 8 wherein said single phase comprises a solution phase.

10. A method as claimed in any preceding claim which comprises a continuous manufacturing method.

11. A method as claimed in any preceding claim wherein the elemental fluorine comprises fluorine gas in admixture with an inert gas.

12. A method as claimed in claim 11 wherein the inert gas comprises nitrogen.

13. A method as claimed in claim 11 or 12 wherein the fluorine comprises in the range from 2-30% of the mixture with the inert gas.

14. A method as claimed in claim 12 wherein the fluorine comprises in the range from 10-15% of the mixture with the inert gas. -

15. A method as claimed in any preceding claim wherein the temperature of reaction is in the range from -25° to +20°C.

16. A method as claimed in claim 15 wherein the temperature of reaction is around -10°C.

17. A method as claimed in any preceding claim wherein the mixture of nitrile and carboxylic acid comprises between 5 and 80% v/v of the carboxylic acid and the remainder nitrile.

18. A method as claimed in claim 17 wherein the mixture of nitrile and carboxylic acid comprises in the region of 10% v/v of the carboxylic acid and the remainder nitrile.

19. A method as claimed in any preceding claim wherein the mixture of nitrile and carboxylic acid is treated with between 0.5 and 5 molar equivalents of fluorine per mole of carboxylic acid.

20. A method as claimed in claim 19 wherein equimolar amounts of fluorine and carboxylic acid are employed.