easier to stir after about one-third of the required amount of
acid was added. When the addition of acid was complete,
the reaction mixture consisted of two clear layers, the bottom
containing the neat product and the upper containing an
aqueous solution of aluminate salts. The upper layer was
siphoned off and the product washed twice with water,
followed by siphoning of the washes. The crude chloromethyl
ether product was suitable for use directly in the subsequent
fluoride exchange.
Experimental Section
Hexafluoro-2-propanol, AlCl , 1,3,5-trioxane, KF, and
PEG-400 were purchased from commercial sources and used
3
as received. GC/MS data were acquired using an HP 6890
gas chromatograph in tandem with an HP 5973 mass-
selective detector and using a Quadrex cyanopropyl methyl
phenyl silicone column. GC analysis was performed using
a Varian 3800 gas chromatograph with a flame ionization
detector (FID) at 300 °C, 280 °C injection, and a helium
gas flow of 2.4 mL/min through a 30-m × 0.55-mm-i.d.
1
Fluoride Exchange
fused silica RTX-1301 capillary GC column. H NMR
spectra were recorded at 300 or 400 MHz on Varian NMR
An earlier method for the conversion of the HFIP-
1
3
specrometers; C spectra were recorded at 75 or 100 MHz.
Chemical shifts are reported in ppm downfield from tetra-
methylsilane (TMS, δ 0.00).
chloromethyl ether into sevoflurane required the use of KF
3
under supercritical conditions. We discovered that the
fluoride exchange could be effected under much milder
conditions, without the need for high temperatures and
pressures (Scheme 2B). In a typical procedure, the crude
product of the chloromethylation reaction was dissolved in
a suitable solvent, dry KF was added, and the mixture was
stirred at 90-95 °C for 1-2 h. When NMP, DMF, or DMSO
was used as solvent, GC/MS analysis of the crude reaction
mixture revealed quantitative conversion to sevoflurane in
each case. However, these solvents tended to darken as the
reaction progressed, and more problematic was the tendency
for the highly fluorinated product to form intractable
complexes with these polar aprotic solvents, making product
isolation difficult. The use of glyme or diglyme as solvent
resulted in very little (<1%) product formation. The most
successful method incorporated poly(ethylene glycol) (PEG)
as the solvent. The fluoride exchange by this method is
remarkably tolerant of a small percentage of water in the
reaction mixture, and since the crude product of the chloro-
methylation does not need to be rigorously dried, the entire
process can be performed in a single vessel. Indeed, a water
content as high as 20% afforded the product, although in
lower (37%) yield. Thus, to the crude product of the
chloromethylation, in the same reaction vessel, was added
PEG-400. The water content of the resultant solution was
determined as 3.2% by Karl Fischer titration. Spray-dried
KF was added in portions, and the reaction mixture was
heated to an internal temperature of 78 °C for 2.5 h, at which
time GC analysis showed the reaction to be complete. The
crude sevoflurane was then distilled directly from the reaction
vessel by gradually heating the mixture from an internal
temperature of 78 to 125 °C. Although sevoflurane boils at
Synthesis of 1,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)-
propane (Sevoflurane, 1). Into a 100-L glass reaction vessel
equipped with an efficient mechanical stirrer, temperature
probe, water-cooled condenser, and cooling coils was placed
3
anhydrous AlCl (8.63 kg, 64.54 mol). Scrubbers containing
water were attached to the reactor to absorb residual HCl
gas produced during the reaction. The reaction vessel was
cooled to 0 °C, and 1,1,1,3,3,3-hexafluoro-2-propanol (11.08
kg, 6.72 L, 64.54 mol) was added in a single portion with
stirring. The mixture was stirred at 0 °C until HCl gas
evolution ceased. To the homogeneous slurry of HFIP and
3
AlCl was added 1,3,5-trioxane (1.94 kg, 21.58 mol) in a
single portion, and the temperature of the reaction was
observed to increase to 8 °C. Stirring was continued for 2 h,
at which point the reaction exotherm had subsided and the
mixture was shown to contain approximately 80% of the
chloromethyl ether 2. The reaction mixture was then allowed
to warm to ambient temperature with stirring overnight. After
2
4 h of reaction, the yield of 2 had increased to over 96%,
as assayed by GC. The reaction mixture was cooled to 0 °C
and stirred vigorously for the careful addition of 26.6 L of
ice-cold 6 N HCl. Stirring became difficult during the highly
exothermic quench, and the aqueous acid was added at such
a rate that the reaction temperature was maintained between
4
0 and 60 °C. When the exotherm had subsided, the
remainder of the acid was added rapidly. Water (10 L) was
added and the solution stirred until two clear phases were
formed. The aqueous portion was siphoned off, and the
organic layer was washed twice with water (10 L). A
distillation receiver was attached to the reaction vessel, and
PEG-400 (32 L) was added to the crude chloromethyl ether
58.5 °C, heating is necessary to decomplex the product from
2
with stirring. The water content of the solution was
the solvent. The addition of water to the reaction mixture
aids in breaking this complex to maximize product recovery.
The crude sevoflurane, as distilled directly from the reaction
vessel, is very pure, containing only a small quantity of water
and the bis(HFIP) acetal as contaminants. After being dried
measured as 3.2% by Karl Fischer titration. Spray-dried KF
was then added in portions to the reaction mixture. The
reaction was heated to an internal temperature of 78 °C for
2
.5 h, at which time all of the chloromethyl ether had been
consumed. The crude sevoflurane 1 (8.73 kg) was distilled
4
over MgSO and distilled through a short (1 ft) Vigreux
column, sevoflurane was obtained in 64% overall yield and
at a purity of 99.4%. We believe that with minor improve-
ments in the reaction apparatus, a yield in excess of 80%
(
4) Sevoflurane purity was redetermined at 99.43% by GC. Proposed yield
improvements include the minimization of evaporative losses throughout
the procedure and the maximization of product recovery from the PEG
solvent. Product purity can be improved by distillation using an increased
number of theoretical plates. The fluoride exchange works well in glass
reactors, although with some etching of the glass by KF. A stainless steel
reactor is more suitable for the process and may also result in increased
yield and purity.
4
and a purity of greater than 99.95% can easily be attained.
(3) Halpern, D. F.; Robin, M. L. U.S. Patent 4,874,901, 1989; Chem. Abstr.
1
990, 112, 157680a.
Vol. 4, No. 6, 2000 / Organic Process Research & Development
•
583