Note: Descriptions are shown in the official language in which they were submitted.
10~526~
This invention relates to a chemical process and more
particularly it relates to a process for the manufacture of
the compound difluoromethyl 1,2,2-trifluoroethyl ether, which
has the formula CHF2-0-CHF-CHF2.
This compound has been described as a by-product
obtained during the fluorination of 1,4-dioxan over cobalt
trifluoride, by Burdon and Parsons in "Tetrahedron" 1971, 27,
4533 to 4551, but the yield (less than 6%) obtained was so
small and the separation so complex that this process is
impractical for the commercial production of the compound.
' Furthermore a process for the manufacture of the compound bythe fluorination of ethyl methyl ether over cobalt trifluoride
has been described by Brandwood et' alia in the Journal of
Fluorine Chemistry, 1975, 5, 521 to 535, but the yield is less
than 1% and it i8 not practical to separate this amount from
the major products of th'is fluorination. A second process
described in this latter publication, the further fluorination
over cobalt trifluoride of monofluoromethyl 1,2,2-trifluoro-
ethyl ether at higher temperature, is also inconvenient for
the commercial production of the compound.
We have now found, and herein lies our invention,
that difluoromethyl 1,2,2-trifluoroethyl ether may conveniently
be obtained in commercially attractive yields from the readily
available tetrafluoroethylene by a number of processes.
According to the invention there is provided a
process for the manufacture of difluoromethyl 1,2,2-trifluoro-
ethyl ether whichcomprises either the reduction of a compound
'' .
i - 2 -
1(~75267
of the formula:-
CF2X-O-CFY-CF2 Z
wherein X is hydrogen, chlorine or bromine, and wherein either
Y and Z, which may be the same or different, each is hydrogen,
chlorine or bromine, provided that X, Y and Z are not all
hydrogen, or wherein Y and Z are joined together to form an
olefinic bond between the two carbon atoms;
or the fluorination of a ccmpound of the f~rmula:-
CHX2X3_o-cHy2-cHzlz2
wherein X2, X3, zl and z2, which may be the same or
different, each is fluorine, chlorine or bromine and wherein
B Y ~is hydrogen, fluorine, chlorine or bromine, provided that
X , X~, y~, zl and z2 are not all fluorine.
The reduction may b~ carried out by means of hydrogen
15 and a catalyst, for example a palladium catalyst, particularly
an 0.5% or 5% palladium-on-charcoal catalyst, and it may
be carried out at a temperature appropriate to the reaction
to be carried out, for example at a temperature of up to 250~C.
Alternatively, the reduction may be carried out by non-catalytic
20 means, for example by means of hydrogen provided by a
dissolving metal, for example by use of sodium or zinc
dissolving in an alcohol, for example methanol, ethanol or
isopropanol~ or by use of a complex metal hydride, for example
-- 3
~075Z67
lithium aluminium hydride or sodium borohydride, in an
appropriate solvent, for example diglyme.
The various starting materials may ~e obtained, as
shown in Figure 1, by a series of reactions starting from methyl
1,2,2-trifluorovinyl ether, which is itself conveniently
obtained from tetrafluoroethylene as follows:-
2 2 + NaOCH3 > CH~0-CF = CF
It is to be understood that in the scheme shown
in Figure 1 two of X, Y and Z may sometimes be the same halogen
atom, in which case the same symbol (Xl or yl) is used in both
positions.
Some of the intermediate compounds described in
Figure 1 are novel compounds. In particular, the compounds
; of the following formulae are novel and are particularly
exemplified herein, and these form further features of the
invention:-
CHC12-0-CFCl-CF2Cl (A)
CHF2-0-CFCl-CF2Cl (B)
CHF2 - o-cF = cF2 ( C )
CHF2-0-CFCl-CEIF2 (D)
CC13-0-CHF-CHF2 (E) t
CF2Cl-0-CHF-CHF2 (F)
CHC12-0-CFCl-CHF2 (G)
and CHC12-0-CHF-CHF2 (H)
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~" 1075267
The fluorination process of the invention may
be carried out using a conventional fluorinating agent.
Thus, for example, a suitable fluorinating agent which
may be used to replace a chlorine or bromine atom x2 or
X3 by fluorine is, for example, antimony trifluoride.
x2 and X3 are preferably both chlorine atoms. A suitable
fluorinating agent which may be used to replace a chlorine
~ or bromine atom y2~ zl or z2 by fluorine i8, for example,
¦ mercuric fluoride. y2~ zl and z2 are preferable all
chlorine atoms. A suitable fluorinating agent which may
be used to replace the hydrogen atom y2 by fluorine is,
~; for example, chlorine trifluoride or bromine trifluoride.
The starting material of the formula CHF2-0-CHY CHF2
~: ~ ;. ` 2
t~ ' wherein Y is hydrogen-or chlorine is a known compound
~ ~ .S`
~ f" 'i'~. ~ 15 ~ ournal of Medicinal Chemistry, 1971, 14, 517 to 519).
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107SZ67
The difluoromethyl 1,2,2-trifluoroethyl ether possesses
valuable anaesthetic properties and may be used in the anaesthetic
composition described and claimed in our copending Canadian Application
Serial No. 250,113.
The invention is illustrated but not limited by the
following Examples:-
Example 1
A stream of hydrogen is passed at the rate of 7650 ml. per
minute through 1,2-dichloro-1,2,2-trifluoroethyl difluoromethyl ether
(48 g.) and the gaseous mixture thus obtained is passed through a
horizontal tube, 60 cm. long and 7.5 cm. in diameter, which contains
a 5% palladium-on-charcoal catalyst (20 g.) heated to a temperature of
between 200 and 250C. The process is continued until all of the ether
has been carried over the catalyst. The gases leaving the tube are
~ passed into a vessel cooled with solid carbon dioxide in acetone.
; The collected liquid is fractionally distilled and there is thus ob-
tained difluoromethyl 1,2,2-tr-fluoroethyl ether (19 g.) b.p. 53-54C.
The 1,2-dichloro-1,2,2-trifluoroethyl difluoromethyl
ether used as starting material may be obtained as follows:-
Chlorine gas is passed through 1,2-dichloro-1,2,2-tri-
fluoroethyl methyl ether (68 g.) which is contained in a 50 ml. radi-
ation cell fitted with a condenser and a solid carbon dioxide in
acetone trap, and which is irradiated by means of a Hanovia* medium
pressure lamp. An exothermic reaction takes place, the internal
temperature rising to 50C. When the weight of the reaction mixture
has increased to 99 g.,
* Trademark
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1075Z67
indicating replacement of two atoms of hydrogen by two atomæ
of chlorine, the reaction i8 stopped and the reaction mixture
fractionally distilled. There is thus obtained dichloromethyl
1,2-dichloro-1,2,2-trifluoroethyl ether, b.p. 127C.
The above material (48 g.) is added slowly to
antimony trifluoride (35.8 g.) which is stirred at 90C., and
the product which distils from the reaction is collected in a
vessel cooled by solid carbon dioxide. The product is
fractionally distilled and there is thus obtained 1,2-dichloro-
1,2,2-trifluoroethyl difluoromethyl ether, b.p. 61-61.5C.
Example 2
A stream of hydrogen is passed at the rate of 750 ml.
per minute over the surface of difluoromethyl 1,2,2-trifluoro-
vinyl ether (25.4 g.) and the gaseous mixture thus obtained is
passed through a horizontal tube, 50 cm.long and 2.5 cm. in
diameter, which contains a 5% palladium-on-charcoal catalyst
(40 g.) supported on small porcelain cylinders (100 g.) and
;~ heated to a temperature of 60C. The process is continued
until all of the ether has been carried over the catalyst.
The gases leaving the tube are passed into a vessel cooled with
solid carbon dioxide in acetone. The collected liquid
(15.6 g.) is fractionally distilled, some starting material
(8.5 g.) being recovered and there is thus obtained difluoro-
~;¢~0~^0~
D methyl 1,2,2-triflùoromc~hyl ether, b.p. 53-54C., in 40% yield
based on the vinyl ether consumed.
The difluoromethyl 1,2,2-trifluorovinyl ether used
as starting material may be obtained as follows:-
1075Z67
1,2-Dichloro-1,2,2-trifluoroethyl difluoromethyl
ether (50 g.) is added dropwise during 30 minutes to a stirred
suspension of zinc dust ~25 g.) and zinc chloride (1.65 g.)
in dimethylsulphoxide (125 ml.) which is maintained at 110C.
The volatile gases which distil out of the reaction mixture
are condensed in a trap cooled with solid carbon dioxide in
acetone. The collected liquid is fractionally distilled and
there is thus obtained difluoromethyl 1,2,2-trifluorovinyl
ether, b.p. 10.5-11C (25.4 g.)
Example 3
A stream of hydrogen at the rate of 500-600 ml. per
minute is passed over difluoromethyl 1,2,2-trifluorovinyl
ether ~50.4 g.) which is cooled to -5C. The gaseous mix-
ture thus obtained is passed through a vertical tube, 45 cm.
long and 2.5 cm. in diameter, which contains 80 g. of an 0.5%
palladium-on-charcoal catalyst heated at 153C. The gases
leaving the tube are passed into a vessel coolet with solid
carbon dioxide in acetone. The collected liquid ~36 g.) is
washed with water and then with saturated aqueous sodium
bicarbonate solution, dried over magnesium sulphate and then
fractionally distilled. There is thus obtained difluoromethyl
1,2,2-trifluoroethyl ether (21.5 g.), b.p. 53-54C.
Example 4
A stream of hydrogen is passed at the rate of 500 ml.
per minute through l-chloro-1,2,2-trifluoroethyl difluoro-
methyl ether (5.7 g.) and the gaseous mixture thus obtained is
passed through a vertical tube, 45 cm. long and 2.5 cm.
_g_
.
1075267
in diameter, which contains an ().56% palladium-on-charcoal
catalyst (80 g.) heated at 240C. The gases leaving the tube
are passed into a vessel cooled with solid carbon dioxide
in acetone. The collected liquid is poured onto ice-water~
5 separated from the water, dried over magnesium sulphate and
fractionally distilled. There is thus obtained difluoromethyl
1,2,2,-trifluoroethyl ether, b.p. 53-54C., in 45% yield.
The l-chloro-1,2,2-trifluoroethyl difluoromethyl
ether used as starting material may be obtained as follows:-
A stream of hydrogen chloride is passed at the
rate of 500 ml. per minute over difluoromethyl 1,2,2-
trifluorovinyl ether (53 g.) which is cooled to -6 C., and
the gaseous mixture thus obtained is passed through a
vertical tube, 45 cm. long and 2.5 cm. in diameter, which
15 contains a catalyst consisting of a 4:1 weight by weight
mixture of granular carbon (10-18 mesh) and calcium sulphate
(8 mesh) heated at 186 C. The reaction is exothermic and
the temperature rises to 229 C. The gases leaving the tube
~re passed into a vessel cooled with solid carbon dioxide
20 in acetone. The collected liquid (42.4 g.) is poured onto
ice-water, separated from the water, dried over magnesium
sulphate and then fractionally distilled. There is thus
obtained l-chloro-1,2,2-trifluoroethyl di~luoromethyl ether
(4.5 g., b.p. 56C.), and later fractions of the distillate
25 consist o~ 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether
(17.5 g., b.p. 56 C.~ used as starting material in Examples 6,
7 and 8) and 1,2-dichloro-1,2,2-trifluoroethyl difluoromethyl
ether (7.9 g., b.p. 61-61.5C.)
. , -- ~.0 --
.. . . .
1075'~67
Example 5
A mixture of l-chloro-1,2J2-trifluoroethyl difluoro-
methyl ether (1.8 g.), zinc (3.5 g.), zinc chloride (0.3 g.)
and absolute alcohol (12 ml.) is heated at 150C. in a sealed,
shaken vessel for 24 hours. The reaction mixture is fractionally
distilled and the distillate boiling within the range 54-
77C. (7.0 g.) is collected. This distillate is further fraction-
ally distilled and there is thus obtained difluoromethyl 1J2~2-
trifluoroethyl ether, b.p. 53-54C., in 40% yield.
Example 6
A mixture of 2-chloro-1,2,2-trifluoroethyl difluoro-
methyl ether ~3 g.), zinc powder (6.5 g.), zinc chloride (0.2 g.)
and absolute alcohol (10 ml.) is heated at 150C. in a sealed
glass tube for 24 hours. The reaction mixture is then fraction-
ally distilled using a Vigreux distillation column, and the
fraction boiling within the range 42-60C. is collected. This
material is further separated into its constitu~nts by gas-liquid
chromatography using a 10% Carbowax* column, and there is thus
obtainet difluoromethyl 1,2,2-trifluoroethyl ether.
Example 7
Sodium metal (0.46 g.) is gradually added to a
stirred mixture of 2-chloro-1,2,2-trifluoroethyl difluoro-
methyl ether (1.8 g.) and absolute methanol (1.0 ml.), and
after the reaction is complete the mixture is filtered and the
filtrate is washed with water and dried over molecular sieve 4A.
The material thus obtained is separated into its constituents
by preparati~e gas liquid chromatography using a 20% Carbowax* 20 M
column at 7~C,, and there is thus obtained difluoromethyl 1,2,2-
* Trade mark -11-
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1075267
trifluoroethyl ether.
Example 8
A solution of sodium borohydride (0.53 g.) in diglyme
(7 ml.) i5 added gradually durin~ thirty minutes to a stirred
mixture Or 2-chloro-1,2,2-trifluoroethyl difluoromethyl
ether (1.85 g.), water (0.9 ml.) and diglyme (4 ml.) which
is maintained at 5C. Water is then added to the reaction
mixture and the lower organic layer is separated, washed with
water and dried over molecular sieve 4A. The material
thus obtained is separated into its constituent parts by
gas-liquid chromatography, and there is thus obtained
di~luoromethyl 1,2,2-trifluoroethyl ether.
Example 9
A stream of hydrogen at the rate of 500-600 ml.
per minute is passed through a mixture of 1-bromo-1,2,2-
trifluoroethyl difluoromethyl ether (4.2 g.) and 2-bromo-
1,2,2-trifluoroethyl difluoromethyl ether (2.0 g.) and the
gaReous mixture thus obtained is passed through a vertical
tube, 45 cm. long and 2.5 cm. in diameter, which contains
80 g. of an 0.5% palladium-on-charcoal catalyst heated at
240C. The gases leaving the tube are passed into a vessel
cooled with solid carbon dioxide in acetone. The collected
liquid is poured onto ice-water and the non-aqueous layer is
separated, dried over magnesium sulphate and then fractionally
distilled. There is thus obtained difluoromethyl 1,2,2-
trifluoroethyl ether, b.p. 53-54~C., in 40% yield.
The mixture Gf di~luoromethyl 1-bromo-1,2,2-
trifluoroethyl ether and di~luoromethyl 2-bromo-1,2,2-tri~luoro-
ethyl ether used as starting material may be obtained as
follows:-
-- 1~ --
.
1075Z67
A stream of hydrogen bromide is passed at a rate
of 500 ml. per minute over difluoromethyl 1,2,2-trifluoro-
vinyl ether (21.3 g.) which is cooled to -8C., and the
gaseous mixture thus obtained passed through a vertical tube,
45 cm. long and 2.5 cm. in diameter, which contains a catalyst
consisting of a 4:1 weight by weight mixture of granular
carbon (10-18 mesh) and calcium sulphate (8 mesh) heated at
158C. The reaction is exothermic and the temperature rises
to 170C. after the passage of gases has continued for 20
minutes. The gases leaving the tube are passed into a vessel
cooled with solid carbon dioxide in acetone. The collected
liquid (15 g.) is poured into ice-water and the organic
layer is separated, dried over magne~ium sulphate and then
fractionally distilled. There is thus obtained a mixture
f l-bromo-1,2,2-trifluo~oethyl difluoromethyl ether (7 g.),
b.p. 72.5C., and 2-bromo-1,2,2-trifluoroethyl difluoromethyl
ether (3.3 g.), b.p. 72.5-73C.
Example 10
Chlorine gas is passed through methyl 1,2,2-tri-
fluoroethyl ether (14 g.) which is contained in a glass
radiation cell fitted with a condenser and a solid carbon
dioxide in acetone trap, and which is cooled in ice-water
B ar~d irradiated by means of a Hanovia medium pressure lamp,
until 17 g. of chlorine have been absorbed. The reaction
mixture is distilled and there is thus obtained a mixture
containing as main components dichloromethyl 1,2,2-trifluoro
1075Z67
ethyl ether, trichloromethyl 1,2,2-trifluoroethyl ether
and dichloromethyl l-chloro-1,2,2-trifluoromethyl ether.
This mixture i5 added dropwise to a stirred mixture of
: antimony trifluoride (20 g.) and antimony pentachloride
(1 ml.) which is heated at 105C., and the product which
distils from the reaction having a boiling point within the
range 53 to 66~C. is collected. This product is fractionally
distilled and there is thus obtained as second fraction
di~luoromethyl 1,2,2-trifluoroethyl ether, b.p. 53-54~.,
yield 23% based on the methyl trifluoroethyl ether starting
material. Another product of the fluorination reaction,
which is the rirst fraction in the distillation, is
chlorodifluoromethyl 1,2,2-trifluoroethyl ether, b.p. 46C.
(yield 20%).
The methyl 1,2,2-trifluoroethyl ether used as
starting material may be obtained as follows:-
A stream Or hydrogen is passed for 2 hours at the
3 rate of 750 ml. per minute over methyl 1,2,2-trifluorovinyl
ether (22 g.) and the gaseous mixture thus obtained is passed
down a column, 16 mm. internal diameter, containing a 1%
palladium on 4-8 mesh granular charcoal catalyst (24 g.).
The gases emerging from the column are condensed in a trap
cooled with solid carbon dioxide in acetone. The column is
then purged with a stream of nitrogen for 18 hours, and the
gases emerging are similarly condensed. The product is
distilled and there is thus obtained methyl 1,2,2-trifluoro-
-- 14 --
107S267
ethyl ether, b.p. 55-57C. (yield, 71%).
Example 11
A mixture of l-chloro-2,2-difluoroethyl difluoro-
methyl ether (5.0 g.) and mercuric fluoride (3.6 g.) is
heated at 115C. in a sealed tube under an atmosphere of
nitrogen for 4 hours. The reaction mixture is fractionally
distilled and there is thus obtained difluoromethyl 1,2,2-
trifluoromethyl ether (1.9 g.), b.p. 53-54C.
