Note: Descriptions are shown in the official language in which they were submitted.
~8~ ;3
- PREPARATION OF ALKYL TRIFLUOROACETOACETATE
The present invention provides the art with a novel and
useful method of preparing alkyl trifluoroacetoacetate by
means of acetylation of a lower alkyl 3-alkoxy-3-hydroxy-
4,4,4-trifluorobutanoate.
It is well known in the prior art to link halogenated
esters with other esters. For example, ethyl trifluoro-
acetoacetate has been prepared by an alkaline condensation
of ethyl acetate with ethyl trifluoroacetate. Upon
neutralization, a reaction product composed of a salt and
the ethanol hemiketal of ethyl trifluoroacetoacetate is
produced which is chemically idantified as ethyl 3-ethoxy-3-
hydroxy-4,4,4-trifluorobutanoate. To convert the hemiketal
to ethyl trifluoroacetoacetate, the hemiketal is hydrolyzed
with ethanol being removed. Unfortunately, this results in
the formation of the hydrate of ethyl trifluoroacetoacetate.
Also, ethanol is formed and discarded as a by-product, thus
making the prior art procedure environmentally and economi-
cally unattractive.
Ethyl trifluoroacetoacetate is useful as an interme-
diate ~or pr paring agricultural chemicals an~ pharmaceuti-
cals. To be best used as such it is usually necessary that
the hydrate form be avoided. Accordingly, in such event the
hydrate of ethyl trifluoroacetoacetate of the prior art must
be dehydrated, which procedure entails an additional and
expensive step. For example in accomplishing the dehydra-
tion, the prior art suggests employing cupric acetate to
form a copper complex of the trifluoroacetoacetate. After
filtration,~ the complex i5 thereafter reacted with hydrogen
sulfide to liberate trifluoroacetoacet~ate which is then
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isolated by distillation. In another prior art procedure,
the trifluoroacetoacetate i5 isolated ~rom the aqueous
medium by solvent extraction and dehydration with deh~dra-
ting agents, for example, calcium chloride, magnesium
sulfate and molecular sieves, with final product distilla
tion.
The present invention provides ~or the convenient and
economic preparation of anhydrous lower alkyl krifluoro~
acetoacetate. Furthermore, alkanols are not produced as a
by-product. Instead, alkyl acetate is formed which can be
recycled and used as a react~nt to form additional alkyl
trifluoroacetoacetate.
In accordance with the present invention, an alkyl 3-
alkoxy-3-hydroxy,4,4,4-trifluorobutanoate is reacted with an
acetylating agent, for example, acetyl halide or acetic acid
anhydride to produce alkyl trifluoroacetoacetate and alkyl
`acetate. The resulting products are isolated one from the
other. The recovered alkyl acetate can be conveniently
recycled for condensation with additional alkyl trifluoro-
acetate to produce the alkyl 3-alkoxy-3-hydroxy-4,4,4-
trifluorobutanoate. The halide may be fluoride, chloride,
bromide, and iodide but preferably chloride. It can be seen
that the more specific and preferred aspects of the present
invention provide a method of preparing C~-C5 alkyl acetate
and Cl-Cs alkyl trifluoroacetoacetate by condensing in the
presence of a strong base condensing agent Cl-C5 alkyl
trifluoroacetate.- Strong bases used to prepare the con-
densation product include sodium metal, sodium ethoxide,
sodium hydride and the like. The condensation product is
neutralized with a strong, essentially anhydrous, mineral
acid including hydrochloric acid, phosphoric acidj sulfuric
acid and the like. Anhydrous hydrochloric acid is pre-
fèrred. The neutralization product, which is alkyl 3-
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4~L~i3
-- 3
alkoxy-3-hydroxy-4,4,4-tri~luorobutanoate (the C1-Cs alkanol
hemiketal of C1 C5 alkyl trifluoroaceto- acetate), is
reacted with acetyl halide or acetic anhydride to produce
C~-C5 alkyl trifluoroacetoacetate, C1-C5 alkyl acetate,
hydrogen halid~ or acetic acid and the salt of the base and
acid. Finally, the aceotacetate, the salt and the acetate
are separated one from the other. The salt can be pre-
cipitated and removed by filtration, centrifugation, solvent
extraction, etc. The acetoacetate, the hydrocJen h~lide or
acetic acid halide and the acetate are conveniently sepa-
rated by fractional distillation or other suitable tech~
niques .
In order to better illustrate the preferred method of
the invention a flow diagram of the method is set ~orth in
the accompanying drawing. At ambient temperature or other
suitable reaction temperature an appropriate amount of a
strong base, such as sodium hydride, preferably as an oil
emulsion, is added to a base-directed condensation zone.
Ethyl trifluoroacetate and ethyl acetate are then metered
into the condensation zone and the reaction mixture stirred.
A suitable inert organic solvent may also be added so that
the reaction can be better controlled and separation o~ the
final product can be facilitated. Suitable solvents
include, for example, cyclohexane, dodecane ethyl ether,
hexane, methyl cyclohexane, l,2-dimethoxyethane, tetra-
hydrofuran, benzene, and the like. The condensation
reaction is initiated in a controlled manner to form the
sodium salt of ethyl trifluoroacetoacetate and ethanol. A
nitrogen gas or other inert gas can be used to sweep and
remove the evolved hydrogen gas.
The resulting reaction mixture is transferred to the
neutralization zone where a strong anhydrous mineral acid,
preferably anhydrous hydrochloric acid, is added, preferably
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-- 4
at 10-15% molar excess to neutralize the reaction mixture
and to form salt and the ethanol hemiketal of ethyl tri-
fluoroacetoacetate. The product o~ neutralization is heated
to remove excess hydrogen chloride as a gas.
Next~ the product of neutralization is flowed into the
acetylation zone where acetyl halide, preferably acetyl
chloride, is reacted therewith to form hydrochloric acid
ethyl acetate and ethyl tri~luoroacetoacetate.
The product of the acetylation step is transferred
into the product separation zone. The salt precipitates and
is filtered or otherwise separated. Ethyl acetate, ethyl
trifluoroacetoacetate, and hydrogen chloride are separated
one from the other by distillation or by other methods.
Thus, ethyl trifluoroacetoacetate is produced as the final
product along with ethyl acetate which may be recycled to
the condensation zone.
An important aspect of the present invention is the
acetylation of the product of the neutralization step. This
product may be ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluoro-
butanoate ~ethanol hemiketal of ethyl trifluoroaceto-
acetate). It was found that upon conventional distillation
of the produck, the hemiketal decomposes to yield ethanol
and ethyl trifluoroacetoacetate. Unfortu~ately, these two
compounds co-distil and recombine in the distillation
receiver to reproduce the hemiketal of ethyl trifluoroaceto-
acetate. Removal of essentially all of the ethanol is
necessary in order to effectively chlorinate ethyl tri-
fluoroacetoacetate, to produce ethyl 2-chlorotrifluoro-
acetoacetate, a chemical found useful as an intermediate for
making certain agricultural chemicals, viz., 2~4-disub-
stituted-5-thiazolecarboxylic acids and derivatives thereof,
- as disclosed in U.S. Patent 4,199,506.
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1284~53
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In the base-directed condensation step, one mole o~
ethyl trifluoroacetate results in the formation of one mole
of ethanol. Therefore, approximately one mole of ace~yl
chloride is required per mole of ethyl trifluoroacetate in
the acetylation step. However, it has been discovered that
using slightly more than one equivalent of acetyl chloride
results in an undesirable amount of the by-product, ethyl 3-
acetoxy-4,4,4-trifluoro-2-butenoate. With 0.80 equivalent
or less the amount of hemiketal in the product is undesir-
ably high. Therefore, it is preferred that about 0.30 to
1.0 equivalent of acetyl chloride per equivalent of the
hemiketal be used in the acetylation step. The use of about
o.95 equivalent of acetyl chloride minimizes formation of
ethyl 3-acetoxy-4,4,4-trifluoro-2-butenoate while minimizing
unreacted hemiketal in the distilled ethyl trifluoroaceto-
acetate.
The base-directed condensation is preferably carried
out in an inert organic medium. Such a medium is conven-
iently provided by the use of inert organic solvents with
the selected alkyl acetate and the selected alkyl tri-
fluoroacetate. Of the suitable solvents mentioned above,
dodecane is the pre~erred solvent. Dodecane has a suf-
ficiently high boiling point to provide excellent separation
of the solvent from the acetoacetate final product in the
distillation step. The amount of solvent employed is not
critical as the use of a solvent can be avoided altogether.
However, the reaction can be better controlled and the
transfer of material from one zone to another is facilitated
by using an organic solvent which is chemically inert in the
process.
The acetylation reaction can be carried out at atmos-
pheric pressure, although pressure employed is not critical.
Thus, the pressure can be lower or higher ~han atmFspheric,
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~Z84~53
if needed to control the reaction or to maintain the react-
ants and product in the desired phase. The temperature ak
which the acylation reaction is conductPd is not of critical
importance. Depending on the particular alkyl trifluoro-
butanoate and the pressure selected, the temperature at
which the butanoate and acetyl halide are brought into
reacting contact may range ~rom about 10C to 115C or
higher.
In regard to the preferred reaction conditions in the
acetylation step, it should be borne in mind that the
reaction of acetyl chloride with ethanol is exothermic.
Normally, the reaction mixture i5 best maintained below 30C
during the initial stage of the reaction during the addition
of acetyl chloride. At this temperature the reaction rate,
as indicated by the evolution of hydrogen chloride, is
relatively slow. With an increase in reaction temperature,
the rate of hydrogen chloride evolution may become undesir-
ably high. In addition, significant losses of volatile
materials may occur due to entrainment thereof in the
hydrogen chloride upon rapid increases in temperature. On
the other hand, if the reaction mixture is held at 30C or
below, the rate of reaction may ~e unacceptably slow. Con-
sequantly, the mixture is gradually heated to reflux to
achieve a controlled and acceptable rate of hydrogen chlor-
ide evolution.
By "lower alkyl" or "alkoxy" it is meant an alkyl
moiety either straight or branched chain having 1-5 carbon
atoms, including methyl, ethyl, n-propyl, isopropyl, meth-
oxy, ethoxy, etc.
The following Examples are presented for illustrative
purposes only and are not intended as a restriction of the
scope of the invention. All parts are given by weight
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unless otherwise designated.
EX~MPLE 1
CONDENSATION
A dry reactor equipped with a heat exchanger, ayitator,
thermocouple, a cooled reflux condenser and mass ~low meter
was charged with 22.3 parts o~ sodium hydride ~60% mineral
oil dispersion) under a nitrogen blanket. The ~low of
nitrogen was minimized to reduce volatility losses. With
stirring, 61.8 parts of dry cyclohexane was added as an
inert organic solvent at room temperature to the sodium
hydride oil dispersion. The stirred contents were then
continuously charged via subsurface with 79.0 parts of ethyl
trifluoroacetate over a 15 minute period. The stirred
slurry W3S then heated to reflux at an atmospheric pressure
to reflux. A Claisen condensation reaction was then ini-
tiated by slowly and continuously adding 53.9 parts of ethyl
acetate at a steady rate over a period of 2 hours. The
reaction rate was controlled by maintaining the reaction
temperature ~etween 45-60C.
After completion of the reaction as indicated by the
cessation of the hydrogen evolution, an additional 55.7
parts of cyclohexane was added to the reaction mixture
containing ethanol and the sodium salt of ethyl trifluoro-
acetoacetate to dilute the mixture.
NEUTRALIZATION
The reaction mixture was transferred to a neutraliza-
tion vessel made up of a reactor fitted with an agitator, a
thermocouple and a cooled reflux condenser. After cooling
the reaction mixture to 25-30C anhydrous HCl (22.3 partsj
was added via subsurface over a period of one hour.
Throughout the HCl addition, the pot temperature was main-
tained below 30C. The resulting slurry was then heated to
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~2~53
reflux at atmospheric pressure and maintained at re~lux to
drive off excess HCl which was vented to a caustic scrubber.
ACETYLATION
The slurry was cooled to 25-30C and 41.5 parts of
acetyl chloride was slowly and continuously added over about
35 minutes, while the temperature of the mixture was kept
below 30C. The mixture thereafter was gradually heated to
reflux at atmospheric pressure and maintained at reflux for
about l 3/4 hours, while approximately 20 parts of HCl
evolved.
PRODUCT SEPARATION
The slurry was maintained at 30C and filtered to
remove precipitated sodium chloride. The resulting salt
filter cake was washed twice with a total of 86.6 parts of
cyclohexane. The wash filtrates werP combined with the
original ethyl tri~luoroacetoacetate-containing filtrate and
the combined material was transferred to a distillation
vessel.
The distillation vessel was equipped with a fractiona-
ting column, a cooled condenser and a product receiver.
Cyclohexane and ethyl acetate were distilled at 32S mm of Hg
absolute and a vapor temperature ranging from 46-71C. This
forecut contained ethyl acetate, which was recycled in sub-
sequent production. Distillation of the second fraction
proceeded at an initial pressure of 325 mm of Hg absolute
and a vapor temperature of 71C and was terminated at a
final pot temperature of 150 1~0C at 20 mm of ~g absolute.
This second fraction (approximately 82 parts) assayed at
94.0 weight percent of ethyl trifluoroacetoacetate. The
yield of ethyl trifluoroacetoacetate was approxlmately 75%.
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EXAMPLE 2
The Example describes the use of dodecane instead of
cyclohaxane as the inert organic solvent. Also, the salt
formed during the neutralization step is removed from the
dodecane by aqueous extraction after ethyl acetate and ethyl
trifluoroacetoacetate have been fractionally distilled.
The rector as described in Example l was charged with
lQ 22 parts of sodium hydride (60% mineral oil dispersion)
under a nitrogen blanket. With stirring 164 parts of dry
dodecane was added at room temperature to the sodium hydride
oil dispersion. The stirred contents were then continuously
charged via subsurface with 74 parts of ethyl trifluoroace
tate over a 15 minute perio~. The stirred slurry was then
heated to 70C. A Claisen condensation reaction was then
initiated by slowly and continuously adding 51 parts of
ethyl acetate at a steady rate over a period of 2 hours.
After completion of the condensation reaction, anhyd~
rous HCl (21.9 parts) was added via subsurface over a period
of one hour. Throughout the HCl addition, the pot tempera-
ture was maintained below 40C. The resulting slurry was
then heated to reflux at atmospheric pressure to drive off
excess HCl.
The slurry was cooled to 58-60C and 40 parts of acetyl
chloride was continuously added via subsurface over one hour
while maintaining a 58-60C pot temperature. The mixture
was gradually heated to reflux at atmospheric pressure and
maintained at these conditions to drive off excess HCl~ The
temperature was then reduced to 75-80C and the mixture was
transferred to a distillation vessel equipped with a frac-
tionating column and a cooled condenser and receiver. The
distillation system was gradually evacuated to 315-320 mm of
Hg absolute. At this pressure the mixture was heated to
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~L284~53
-- 10 --
reflux to establish equilibrium in the column. The ethyl
acetate forecut was then distilled and collected in a cooled
receiver. Throughout the distillation the pot temperature
gradually was increased. When the vapor temperature reached
75C (approximately 51 parts distillate being collected),
the forecut receiver was isolated and drained into a con-
tainer. This forecut was recycled. Distillation o~ the
second fraction proceeded at an initial pressUre o~ 315-320
mm Hg absolute and the pressure was rapidly decreased during
the distillation of this fraction to a final pressure of 40
mm Hg absolute. The final pot temperature was 130C. The
yield of ethyl trifluoroacetoacetate in the s~cond cut was
about 80%.
The distillation pot residue was washed with 209 parts
of water with agitation. The mixture was allewed to separ-
ate into an aqueous layer and an organic layer. The aqueous
layer containing the sodium chloride was drained and sent to
waste. A second water extraction was carried out in a
similar manner. The organic layer containing the dodecane
was purified for reuse by distillation.
EXAMPLE 3
This Example illustrates the preparation of ethyl tri-
fluoroacetoacetate wherein sodium ethoxide is the strong
base used to condense ethyl acetate and ethyl trifluoroace-
tate.
A suitable flask was charged with 71.05 parts of ethyl
trifluoroacetate and 57.33 parts of ethyl acetate. With
rapid stirring, 34.04 parts of sodium ethoxide was added
slowly so as to keep the reaction mass below 35C. The
` mixture was heated at reflux at atmospheric pressure for two
hours. The reaction mixture was cooled to room temperature
and was neutralized with 21 parts of anhydrous hydFochloria
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acid with the temperature being maintained below 40C.
Sodium chloride precipitated duriny the neutralization.
Next, the pressure in the flask was reduced to 100 mm Hg
absolute to remove unreacted hydrochloric acid. Next, 78.5
parts of acetyl chloride was added dropwise over a one hour
period to the reaction mixture. After complete addition of
the acetyl chloride the pressure was reduced to 100 mm of Hy
absolute to remove the hydrogen chloride formed duriny the
acetylation reaction. The resulting product was ~raction-
ally distilled at reduced pressure. An analysis of the
distillation product showed an ethyl trifluoroacetoacetate
yield of 59~. No hemiketal was present in the distillation
product as determined by 1~F NMR.
EXAMPLE 4
This Example illustrates ths preparation of n-butyl
trifluoroacetoacetate.
An appropriate three neck flask was charged with 40
parts of n-butyl trifluoroacetate, 32 parts of n-butyl
acetate, and 100 parts of dodecane. With stirring 5.9 parts
of sodium metal was added to the reaction mixture. The
temperature of the mixture gradually rose to 55C over a 20
minute period. The temperature was controlled at 55C for
one hour using a cold water bath. Thereafter, the reaction
mixture was heated to 95-90C and held at this temperature
for 75 minutes to assure completion of the reaction. Next,
23.5 parts of sulfuric acid (85-98%) was added dropwise to
the reaction mixture with stirring. The temperature of the
mixture was controlled at 25-30C using a cold water bath.
After addition of the sulfuric acid, 18 parts of acetyl
chloride was added dropwise over a period of five minutes to
the reaction mixture with the temperature being controlled
at 25-30C. The resulting mixture was a slurry with sodium
chloride. The volatiles were removed by straight takeover
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vacuum distillation. The distillate was ~ractionally dis-
tilled to produce lo parts o~ n-butyl tri~luoroacetoacetate,
the chemical structure of which was confirmed by NMR tech-
niquas and elemental analysis.
Although this invention has been described with respect
to specific embodiments, the details thereo~ are not to be
construed as limitations, ~or it is apparent that various
equivalents, changes and modifications may be made without
departing ~rom the spirit and scope thereof. It is under-
stood that such equivalent em~odiments are intended to be
included herein.
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