Method of synthesizing fluoromethylhexafluoroisopropyl ether

A method of synthesizing fluoromethylhexafluoroisopropyl ether comprises adding hexafluoroisopropyl alcohol to a mixture comprising a stoichiometric excess of paraformaldehyde and hydrogen fluoride, plus sufficient sulfuric acid to sequester most of the water produced by the reaction. The mixture is maintained at a temperature of at least 57.degree. C., to cause vapor formation by boiling of the fluoromethylhexafluoroisopropyl ether formed. The vapor is then collected and condensed, and may be purified by distillation.

BACKGROUND OF THE INVENTION 
Fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, as described in U.S. 
Pat. Nos. 3,683,092 and 3,689,571, is a promising new anesthetic for human 
use which is essentially non-inflammable, and appears to have few or no 
undesirable side effects when administered to humans. 
In the abandoned U.S. patent application Ser. No. 771,365, filed Oct. 28, 
1968, from which the above two patents claim priority, several techniques 
are suggested which may be used for making ethers having halogen groups in 
both of the organic ether substituents, including 
fluoromethylhexafluoroisopropyl ether. It is suggested there that the 
corresponding alcohol may be reacted with formaldehyde and hydrogen 
fluoride to form the fluoromethyl ether. However, yields of this reaction 
generally described in the abandoned patent application cited above, are 
not of a desired commercial scale, so other, more cumbersome, multiple 
step synthesis routes were initially preferred. Weynmayr U.S. Pat. No. 
2,992,276 also teaches the use of paraformaldehye and hydrogen fluoride as 
a reagent for synthesizing a fluoromethylether and an alcohol from 
tetrafluoroethylene. 
In accordance with this invention, a simplified, high yield synthesis 
technique for fluoromethylhexafluoroisopropyl ether is disclosed, capable 
of producing yields of the desired ether product of the order of 90 
percent, with recycling of unused reactants through the reaction mixture 
for optimization of synthesis. Particularly, 
fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether may be made this way as 
a clinical anesthetic on a large scale basis. 
DESCRIPTION OF THE INVENTION 
In accordance with this invention, fluoromethylhexafluoroisopropyl ether 
may be synthesized by adding 1,1,1,3,3,3-hexafluoroisopropyl alcohol to a 
mixture containing a stoichiometric excess of formaldehyde (preferably 
paraformaldehyde) and hydrogen fluoride, plus sufficient sulfuric acid to 
sequester most of the water produced by the reaction. The reaction mixture 
is maintained at a temperature of at least 57.degree. C. (which is the 
boiling point of fluoromethyl-1,1,1,3,3,3- hexafluoroisopropyl ether) to 
cause vapor formation by boiling of the ether product formed. Accordingly, 
the ether product which is formed is quickly removed from the reaction 
mixture by boiling, which greatly reduces degradation of the ether product 
by the strongly acidic reaction mixture. 
The vapors of the ether product are then collected and condensed, for 
example with conventional distillation equipment, to collect the impure 
fluoromethylhexafluoroisopropyl ether product. Thereafter, the ether 
product may be purified, preferably by a conventional distillation 
technique, with the hexafluoroisopropyl alcohol wich is co-distilled with 
the ether product being returned, if desired, to the reaction mixture. The 
deuterium-containing analog of the above alcohol may be used if desired, 
or deuterated formaldehyde, to form a deuterated ether product. 
Byproducts of the reaction may also be removed by conventional 
distillation, or other known purification techniques. 
The term "formaldehyde" as used herein is intended to include polymers 
thereof as well as the monomer, such as trioxane or the preferred 
paraformaldehyde. 
Preferably, the temperature of the reaction mixture is maintained at 60 to 
70 degrees, with the hexafluoroisopropyl alcohol being added on a 
continuous, gradual basis. This permits the rapid distillation of the 
ether product, which is rapidly distilled out of the reaction mixture, and 
the codistilled alcohol reactant being returned to the mixture after 
separation from the ether product, until the formaldehyde and hydrogen 
fluoride reactants become reduced to a concentration insufficient to 
provide the desired high yields of ether product. 
Preferably, at least a 10 to 100 percent molar excess of formaldehyde is 
present in the reaction mixture, based on the total amount of the 
hexafluoroisopropyl alcohol added. 
Also, at least a 400 to 1000 percent molar excess of hydrogen fluoride is 
preferably present, based upon the total amount of hexafluoroisopropyl 
alcohol added. 
It is also preferable for a greater weight of generally anhydrous 
(preferably at least 95 percent) sulfuric acid to be present, when 
compared with the total weight of the formaldehyde present. Preferably, 
from 50 to 200 percent greater weight of the generally anhydrous sulfuric 
acid is present. 
It is also contemplated that other ingredients such as solvents, catalysts, 
diluents, and other materials may also be present in the reaction mixture 
if desired, as long as the added extraneous materials do not materially 
change the nature of the reaction described above, but are added to 
promote the reaction, suppress side reactions, improve the purification 
step of the synthesis, etc. 
The example described below is presented for illustrative purposes only, 
and is not intended to limit the scope of the invention of this 
application, which is as defined in the claims below. 
EXAMPLE 
To 3.0 grams by weight (0.1 mol) of paraformaldehyde there was added 5 ml. 
of 96 percent sulfuric acid and 10 grams (0.5 mol) of hydrogen fluoride. 
This reaction mixture was heated to 65.degree. C. Thereafter, there was 
added on a dropwise basis, over one hour, 13.4 grams (0.08 mol) of 
1,1,1,3,3,3-hexafluoroisopropyl alcohol. 
During this period, vapors were generated on the dropwise addition of the 
alcohol reactant, which vapors were collected in a cooled collector of a 
distillation set over a period of two hours, using the nitrogen sweep 
technique and apparatus shown in FIG. 1 and described below. 
Thereafter, the material obtained in the cooled collector at the end of the 
two hours was quenched on ice, neutralized with ammonia, and distilled. 
The material from the cooled collector gave two fractions on distillation. 
Fraction (1) distilled between 25.degree. and 58.degree. C., to provide a 
yield of 6.7 grams of material. Fraction (1) was found upon analysis to 
yield 90 percent by weight fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl 
ether, 3 percent by weight of the initial alcohol reaction material, and 7 
percent of a formal byproduct, the analysis being by Gas Chromatographic 
Analysis. 
Fraction (2) from the cooled collector distilled between 58.degree. and 
95.degree. C. to yield 5.5 grams of material. This fraction contained 11 
percent by weight of fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, 
42 percent of the alcohol starting material, 33 percent of a formal 
byproduct, and 13 percent of an acetal byproduct, the analysis being again 
by Gas Chromatographic Analysis. 
It appears that the fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether can 
be obtained in greater than a 90 percent yield, at between 33 and 38 
percent conversion, based upon the recovered alcohol reactant from 
fraction (1). It is, however, also possible that some water may azeotrope 
during the distillation process, which may tend to suppress the yields. 
This can be controlled to a significant extent by the concentration of 
sulfuric acid present, which can sequester water that is formed in the 
reaction. 
The recovered alcohol reactant and byproducts are readily separable from 
the ether product, and then may be recycled back to the reaction mixture 
for the production of more ether product.

Referring to FIG. 1, reaction vessel 10, made of Kel-F fluorinated plastic 
and sealed with closure 12, defines an inlet line 14 which has a branch 
connection. One of the connections 16 is connected to a source of 
pressurized nitrogen gas, and the other connection 18 is connected to a 
source of hexafluoroisopropyl alcohol. The reaction vessel 10 is equipped 
with a magnetic stirring bar 20, and positioned within an oil bath 22 for 
control of the temperature of the reaction mixture at, preferably, about 
65.degree. C. 
Tubular outlet line 24 communicates with container 10 and carries vapors 
generated by the reaction mixture 26, which contains the paraformaldehyde, 
hydrogen fluoride, and sulfuric acid reactants, to a collector container 
28 made of Kel-F fluorinated plastic. Container 28 also defines closure 30 
with line 34 sealingly passing through it. Container 28 is also placed in 
a cooling bath 32 to assist in condensation of the vapors in container 32. 
Vent line 34 communicates with the exterior. Accordingly, nitrogen gas may 
be constantly used to provide a low velocity gas sweep through the 
reaction system, while the alcohol reactant is added dropwise through 
inlet line 18. The vapors which are generated leave reaction chamber 10 
through line 24, and are condensed in container 28. The sweeping nitrogen 
gas then continues to pass outwardly through vent 34, while the products 
and byproducts of the reaction are collected in the collector container 
28. 
Periodically, the collector container 28 may be empties of its contents, 
with the ether product being purified and separated from the alcohol 
reactant and its byproducts. The reactant and byproducts may be returned 
to the reaction mixture for further production of the ether product. The 
byproducts, in turn, tend to suppress the creation of more byproducts in 
the reaction mixture by the principles of chemical equilibrium. 
Alternatively, they may be separated for use or further processing.