Title: SINGLE POT PROCESS TO PREPARE ETHYL 2, 2-DIFLUOROACETATE
Field of Invention:
The present invention relates to a one pot process for the manufacture of Ethyl 2, 2-
Difluoro Acetate.
Background of the Invention and prior arts:
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FYJV^CH3
F
Ethyl difluoroacetate (ethyl 2,2-difluoroacetate) is a fine chemical product with the
molecular formula C4H6F2O2. It is a colorless transparent liquid with a sweet odor;
insoluble in water and boiling at 97 °C.
Ethyl difluoroacetate is mainly used as agrochemicals intermediate or pharmaceuticals
intermediate to produce agrochemicals & animal nutrition, health, personal and home
care products.
Ethyl difluoroacetate is also used in preparing pyrrazolo-pyrimidine derivatives. For
instance,7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3
carboxylic acid is made from a stirred solution of ethyl difluoroacetate in tert-butylmethyl-
ether with a solution of sodium methanolate in methanol and a solution of
commercially available 4-trifluoromethyl-acetophenone in tert-butyl-methyl-ether.
Various attempts have been made to prepare ethyl difluoroacetate (EDFA) with
enhanced industrial applicability and high yields.
Some of the known processes for the preparation of ethyl difluoroacetate are as
discussed in the preceding paragraphs.
2
US 2012/0123159 teaches a method for preparing difluoroacetic acid wherein the
method includes reacting a difluoroacetic acid ester with an aliphatic carboxylic acid
which, after transesterification, results in the formation of difluoroacetic acid and the
corresponding carboxylic acid ester, the carboxylic acid being selected such that the
ester of the carboxylic acid has a lower boiling point than that of difluoroacetic acid; and
removing the ester of the carboxylic acid by distillation as the ester forms, thus enabling
the Difluoroacetic acid to be recovered. By way of prior arts, it has further been
discussed in this cited document that difluoroacetic acid maybe prepared by, in
accordance to a route as described in EP-A 1 137 615, which consists in carrying out
the hydrogenation / dehalogenation of chlorodifluoroacetic acid by hydrogenation in a
basic medium in the presence of a particular Raney Nickel. Further in JP-A 6228043, a
process is disclosed to prepare a difluoroacetic acid by basic hydrolysis of an N, Ndialkyldifluoroacetamide
obtained by the reaction of dichloroacetyl chloride and a
dialkylamine. It has been also observed that it is very difficult to purify difluoroacetic acid
obtained in aqueous solution as this is a product which is soluble in water and under
these conditions, more difficult to separate by distillation. The objective of developing a
method of preparation of difluoroacetic acid in this cited document was to improve upon
such drawbacks as described in this paragraph.
WO 2012/062602 A1 teaches a process for the preparation of difluoroacetic acid from
tetrafluoroethylene. The process comprises reacting tetrafluoroethylene with an
aqueous solution of an inorganic base, optionally in the presence of an organic solvent.
In the prior art discussion of WO 2012/062602 A1, JP 07 242587 (ASAHI GLASS CO
LTD), 19.09.94 teaches a preparation of difluoroacetic acid by a two-step process
wherein tetrafluoroethylene is reacted with a primary or secondary amine in the
presence of water and, optionally, a tertiary amine to obtain a difluoroacetamide of
formula CHCF2CONRiR2 which is then hydrolyzed to difluoroacetic acid in the presence
of concentrated acids or alkalis. The objective of the WO 2012/062602 is a process for
the preparation of difluoroacetic acid comprising reacting tetrafluoroethylene with an
aqueous solution of an inorganic base.
c
US 5,710,317 teaches a method for preparing difluoroacetic acid fluoride, which
comprises reacting a 1-alkoxy-1,1,2,2-tetrafluoroethane of the formula HCF2CF2OR1
wherein R1 is a C1-4 alkyl group in a gas phase in the presence of a metal oxide catalyst.
The objective of US 5,710,317 was to improve upon the drawbacks in the document J.
Am. Chem. Soc. 72, 1860 (1950), wherein a method for wherein a 1-alkoxy-1, 1, 2, 2
tetrafluoroethane is reacted with sulfuric acid and silica.
US 2012/0190884 A1 teaches a method for preparing difluoroacetic acid esters which
can include reacting difluoroacetyl fluorine with an aliphatic or cycloaliphatic alcohol in
the presence of a heterogeneous mineral base. The object of this invention is primarily
to prepare an ester of difluoroacetic acid, characterized in that it comprises the reaction
of difluoroacetyl fluoride with an aliphatic or cycloaliphatic alcohol, in the presence of a
heterogeneous mineral base.
US 8,299,300 teaches a method for preparing difluoroacetic acid and the salts thereof.
The invention also relates to the preparation of difluoroacetyl fluoride used as an
intermediate product in the preparation of difluoroacetic acid. The method for preparing
difluoroacetic acid according to the invention comprises the step of preparing
difluoroacetyl fluoride by reacting dichloroacetyl chloride with hydrofluoric acid in
gaseous phase and in the presence of a chromium-based catalyst, followed by the step
of hydrolyzing the difluoroacetyl fluoride thus obtained.
The processes as disclosed in the prior arts suffers from a number of drawbacks,
wherein ethyl difluoroacetate is achieved in poor yields and various difficulty faced in
purification of the end product. Further, in some cases, the processes comprised of
unnecessary number of steps of production leading to high costs.
The inventors of the present invention has attempted to introduce an industrially
feasible, cost effective, environment friendly and moreso a process comprises simple
steps with high productivity of the end product. A significant drawback of the prior arts
has been the proper and effective recovery of the hydrofluoric acid in the processes,
which came across to be the single most difficult step. The Applicants of the present
7
invention have attempted to overcome this step as well by introducing relatively easy
step of recovery.
Objective of the present invention:
The object of the present invention relates to an industrially feasible and cost effective
one pot process for the manufacture of ethyl 2,2 difluoroacetate with a recovery step of
hydrofluoric acid.
Detailed Description of the Invention:
The present invention relates to a one pot process for manufacture of ethyl
difluoroacetate from tetrafluoroethylene with enhanced industrial applicability and high
yields and low fluoride content.
1, 1, 2, 2-Tetrafluorethyl-N, N-dimethylamine (TFEDMA) is prepared as per literature
reference; "Journal of Fluorine Chemistry", Vol. 109, 2001, pg. 25-31.
CF*=Ch + (CHihNH •» HCIOTiPih
Tetrafluoroethylene + Dimethyiamine -> TFEDMA
It is widely known as well as disclosed in Petrov et al that, TFEDMA reacts with water to
form 2,2-Difluoro-N,N-dimethyl acetamide (DFDMA) with release of 2 moles of HF.
CHF2CF2N(CH3)2 + H p •* CHF2C(0)N(CH3)2 + 2HF
Accordingly, as shown above, water was added to TFEDMA drop wise at temperature
ranging from 5°C to 80°C to TFEDMA and converted it to DFDMA. The objective herein
was to strip off all the HF generated from the reaction mixture and to recover the same.
J?
However, it is observed that 50% of the HF released during the reaction with TFEDMA
and water, forms a complex with DFDMA, which is a weak base, while most of the other
50% remains dissolved in the reaction mixture at the reaction conditions. Another
problem which was observed herein was that, while it is relatively simple to strip the
dissolved HF by heating and bubbling nitrogen through the liquid, the other half of the
HF which remains complexed with DFDMA is not easy to strip completely and recover.
As explained in the preceding paragraph, the hydrogen fluoride bound with 2, 2-
difluoro-N.N-dimethyl acetamide as a salt cannot be removed by heating. Therefore, for
the removal of this aforementioned bonded hydrogen fluoride from the 2,2- difluoro-N,Ndimethyl
acetamide, an acid stronger than hydrogen fluoride is required. Sulfuric acid
was found to be preferably suited for this purpose, wherein the hydrogen fluoride bond
is replaced with sulphate bond. The pKa value of hydrofluoric acid is 3.14 (Ka -7.2 X 10"
4) whereas, for sulfuric acid, the pKa value is less than 1 resulting in the higher acidity of
sulfuric acid. Owing to sulfuric acid being more acidic than hydrofluoric acid, sulfuric
acid is a preferred choice for the mineral acid to be used herein for the removal of
hydrofluoric acid.
The pKa value of HCI, HBr and HI is also less than 1 but these acids contain water,
therefore making sulfuric acid the reagent of preference. Further the water content of
the other mineral acids would have hampered the conversion step in the reaction
wherein the conversation could not have been completed in the presence of water. So
for complete conversion of amide to ester, reaction should be carried out in anhydrous
condition. Thus sulfuric acid was selected which have pKa value less than 1 and
maintained the anhydrous condition in the reaction mass.
Sulfuric acid is further useful for esterification step as well. The mineral acid with a pKa
value of less than 1 may also be selected from a group of Nitric acid (HN03), Chloric
acid (HCI03) and Perchloric acid (HCI04).
Therefore, instead of attempting to recover HF at this stage, 100% H2SO4 at 10% molal
excess was added with respect to DFDMA. The sulphuric acid surprisingly, displaced
6
HF from DFDM: HF complex and, presumably, formed DFDMA: H2S04 complex as
below;
CF2CO(CH3)2N:HF+H2S04 •> CFiCOPifeNirUSCfc + HF
During heating in presence of sulfuric acid, which has the characteristic pKa value, the
N-F bond breaks and the N-HSO4 bond will form resulting in the liberating of HF from
DFDMA. A concentration of approximately less than 500 ppm of HF is observed after
the reaction duration of 20 hrs.
The liberated HF was released as dense white fumes from the reaction mass at a
temperature range of about 90°C to 110°C. Upon bubbling of nitrogen gas through the
reaction mixture, almost all the HF could be stripped off and recovered in about 12-14
hours.
The reaction mass now contained DFDMA: H2S04 complex along with 10% molal
excess of H2SO4. The fluorides measured as HF was less than 500 ppm. The desired
range of concentration of fluorides as HF is between 100-500 ppm.
To the reactor, absolute ethanol was added drop wise at about 100°C under agitation to
the DFDMA: H2S04 complex under refluxing condition. Ethyl Difluoroacetate (EDFA)
and Dimethylamine Sulphate (DMA: H2S04) is formed.
CFjCOfCHjhNtflSCM + C2HsOH -> CF*COOC*HS • (CHi)2N:H2S04
DFDMA: H2S04 + Ethanol -> EDFA + DMA:H2S04
An important embodiment of the present invention is to provide for alcoholysis of the
DFDMA: H2S04 with absolute ethanol under the experimental condition of drop wise
•?-
addition of C2H5OH (absolute ethanol) at about 100°C under agitation and refluxing
condition.
The crude EDFA is then distilled from the reaction mixture completely leaving behind
dimethyl amine sulphate and sulphuric acid. In one embodiment, the recovered crude
EDFA contained 97.3 % wt EDFA along with 1.32% un-reacted Ethanol and about
1.396% Diethylether. The EDFA in the crude mixture accounted for about 92.5% TFE
initially taken.
Further, dimethyl amine (DMA) can be recovered from the dimethylamine sulphate by
neutralizing it using slaked lime. The mixture of dimethylamine sulphate and sulfuric
acid remaining after recovery of crude EDFA is added slowly to slaked caustic slurry
kept under agitation. The dimethylamine liberated is distilled out and absorbed into
water maintained at about 5°C. Thus, almost 90% dimethylamine may be recovered as
40% dimethylamine solution in water which may be commercialized, or further distilled
to anhydrous dimethylamine and recycled to the process.
A more specific embodiment of the single pot process of the present invention is as
below.
In an embodiment of the present invention, a single pot process for preparation of ethyl
2, 2-difluoroacetate is provided, said process comprising of the steps of:
a) treating tetrafluoroethylene with dimethylamine to achieve 1, 1, 2, 2
tetrafluoroethylene - N,N dimethylamine, followed by adding water to produce
2, 2 - difluoro N,N dimethyl acetamide;
b) treating the 2, 2 - difluoro N,N dimethyl acetamide of step (a) with a mineral
acid having a pKa range of 3.14 to less thanl, at an elevated temperature in a
range of 50°C to 150°C to form an acetamide-acid complex with a fluoride
content in a range of 500 ppm to 100 ppm ;
c) adding an alcohol at an elevated temperature range and under reflux
condition to achieve ethyl 2,2 difluoro acetate followed by distillation for
recovering dimethylamine.
B
In another embodiment of the present invention, the pKa value of the mineral acid is in a
range of 3.08 to less than <1, preferably in a range of 0.8 to 0.1.
In yet another embodiment of the present invention, the mineral acid is selected from a
group of hydrochloric acid, hydrofluoric acid and sulfuric acid, preferably sulfuric acid.
In one more embodiment of the present invention, the alcohol in step (c) is a C1-C4
alcohol, preferably ethanol. The temperature in step (b) is in a range of 50°C to 150°C
under inert conditions. Secondary amine use for making acetamide is a C2-C8 having
linear or branched, preferably dimethyl amine.
The free fluoride content was analyzed by conventional method using Orion meter.
The present invention will be further clear from the working examples provided in order
to carry out embodiment of the present process of preparing ethyl 2,2-difluoroacetate
with a fluoride content of 500 to 100 ppm.
Working examples:
Example 1:
Single Pot Synthesis for produce Ethyl 2,2-difluoroacetate from 1,1,2,2-Tetrafluoroethyl-
N,N-dimethylamine
Step 1: Synthesis of 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine
Connecting the tetrafluoroethylene and dimethyl amine cylinder to 5.0 lit high pressure
hastelloy C autoclave, followed by purging with inert nitrogen, and applying vacuum for
removing the oxygen from the autoclave. Further connecting the autoclave vent to
caustic scrubber and circulating brine solution to autoclave to bring down the
temperature below 5.0°C.470.0 gm (10.44 moles) of dimethylamine is charged slowly in
the autoclave by keeping the DMA cylinder on weighing balance. Tetrafluoroethylene is
added slowly to the autoclave with continuous stirring and maintaining the temperature
of autoclave between 0-5°C. The total amount of 1034 gm (10.33 moles) of tetrafluoro
1
ethylene is charged within 8-10.0 hrs. The pressure of the reactor may be maintained at
3.0 to 3.5 Kg, keeping the autoclave temperature at 5.0°C for another 3.0 hours to
complete the consumption of tetrafluoroethylene and dimethyl amine. The temperature
of the autoclave is slowly raised up to 15.0°C, keeping the autoclave vent attached to
scrubber and purging the autoclave with nitrogen to remove any un-reacted gases for
the autoclave. The quantity of 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine thus
achieved is 1500 gm and yield is 98.79% and conversion of tetrafluoroethylene is 100%
. Purity by GC analysis is 98.79% and 1.01 % amide.
Step 2: Synthesis of 2, 2-difluoro-N,N-dimethyl acetamide
Keeping the autoclave vent attached to caustic scrubber and without withdrawing the
product form the autoclave, added water 186.0 gm(10.33 mol) during the period of 2.0
hours, maintaining the temperature between 25-30°C with flow of 10-15 ml/min of
nitrogen so that liberated hydrofluoric acid is scrubbed by way of the caustic scrubber.
In scrubber, 5.0 kg of 10% sodium hydroxide solution used for scrubbing liberated
hydrofluoric acid. After completion of this reaction, water is added by stirring, while the
temperature of the autoclave is maintained at 25.0°C for 1.0 hour with 10-15 ml/min of
nitrogen in order to remove the liberated hydrofluoric acid from the product. After
completion of reaction the concentration of caustic scrubber is observed at 5.6% as
sodium hydroxide. The weight of the 2,2- difluoro-N,N-dimethyl acetamide is 1572 gm
and acidity as hydrofluoric acid is 19.5 %. Yield is 99.5% as amide.
Step 3 (A): Synthesis of Ethyl 2,2-difluoroacetate in presence of high
concentration of hydrogen fluoride
In hastelloy C autoclave 1572 gm of 2,2-difluoro-N,N-dimethyl acetamide is added to
19.5% of hydrofluoric acid (100% bases 1265 gm 10.30 mole). Slowly increased the
temperature of 2,2- difluoro-N,N-dimethyl acetamide up to 153°C within 5.0 hours with
steady flow of 0.2 ml/min Nitrogen and at 150 mm/Hg vacuum applied for removal of
free hydrofluoric acid while maintaining the same temperature for a further 15.0 hrs.
Caustic scrubber is continued to be attached with the vent line of the autoclave. After
/D
20.0 hours, sample was analyzed for fluoride content and 14.05% hydrogen fluoride
was observed. Means bounded hydrofluoric acid cannot be removed withy sulfuric acid.
Maintaining the temperature upto 60°C, to the above acetamide, add 1149 gm (11.72
mole) sulfuric acid is slowly added with stirring, over a period of 2.0 hours and slowly
increase the temperature up to 90°C and 470 gm (10.20 mole) of ethanol is added over
a period of 6.0 hours with stirring. The same temperature is maintained for a further 8.0
hours followed by distilling out the crude Ethyl 2,2-Difluoroacetate from autoclave at
maximum temperature of autoclave at 130-140°C. During the distillation, free hydrogen
fluoride is liberated along with the reaction product. The crude ethyl 2,2-difluoroacetate
obtain 1015 gm with 88.3% purity by gas chromatography and high acidity observed as
hydrogen fluoride.
Step 3 (B): Synthesis of Ethyl 2,2-difluoroacetate
1572 gm of 2,2-difluoro-N,N-dimethyl acetamide is treated to 19.5% of hydrofluoric acid
(100% bases 1265 gm 10.30 mole). The temperature of 2,2-difluoro-N,N-dimethyl
acetamide is increased to 60°C and 1162.0 gm (11.84mole) of sulfuric acid is slowly
added with stirring ,over a period of 2.0 hours, such that the temperature remains
between 60-70°C. After addition of sulfuric acid raise the autoclave temperature up to
110°C with 0.2 ml/min Nitrogen flow and 150mm/Hg vacuum apply for removal of free
hydrofluoric acid form 2,2-difluoro-N,N-dimethyl acetamide. After 20.0 hours the free
fluoride is observed to drop below 100 ppm. After removing the fluoride from acetamide
the temperature is brought down to 90°C and started addition of 470 gm (10.20 mole) of
ethanol over a period of 6.0 hours with continuous stirring. The same temperature is
maintained for further 8.0 hrs. The crude ethyl 2,2-difluoroacetate is distilled out from
autoclave keeping at maximum temperature of autoclave at 130-140°C. The crude ethyl
2,2-difluoroacetate obtain 1140 gm with 90.4% purity by Gas chromatography.
Step 3 (C): Synthesis of Ethyl 2,2-difluoroacetate
/ /
1572 gm of 2,2-difluoro-N,N-dimethyl acetamide is treated to 20.15% of hydrofluoric
acid (100% bases 1255 gm 10.19 mole). The temperature of 2,2-difluoro-N.N-dimethyl
acetamide is increased to 60°C and 1162.0 gm (11.84mole) of sulfuric acid is slowly
added with stirring ,over a period of 2.0 hours, such that the temperature remains
between 60-70°C. After addition of sulfuric acid raise the autoclave temperature up to
110°C with 0.2 ml/min Nitrogen flow and 150mm/Hg vacuum apply for removal of free
hydrofluoric acid from 2,2-difluoro-N,N-dimethyl acetamide. After 22.0 hours the free
fluoride is observed to drop below 200 ppm. After removing the fluoride from acetamide
the temperature is brought down to 90°C and started addition of 467 gm (10.09mole) of
ethanol over a period of 6.0 hours with continuous stirring. The same temperature is
maintained for further 8.0 hrs. The crude ethyl 2,2-difluoroacetate is distilled out from
autoclave keeping at maximum temperature of autoclave at 130-140°C. The crude ethyl
2,2-difluoroacetate obtain 1118 gm with 90.4% purity by Gas chromatography.
Step 4: Recovery of Dimethyl amine
After recovering the crude ethyl 2,2-difluoroacetate, the remaining mixture contains
dimethyl amine sulphate in the autoclave. The amine sulphate is cooled to a
temperature of 40.0°C and start addition of 18% sodium hydroxide solution 2638 gm
(475 gm, 11.87 moles). During the addition dimethyl amine is liberated from the
condenser vent which is collected by circulation of brine to condenser and scrubbed in
water. The weight of 40% dimethyl amine solution obtained 1047 gm on 100% bases
409 gm of dimethyl amine recovery, it is 87.0% recovery from starting.
/z

We Claim:
1. A single pot process for preparation of ethyl 2, 2-difluoroacetate, said process
comprising of the steps of:
a) treating tetrafluoroethylene with dimethylamine to achieve 1, 1, 2, 2
tetrafluoroethylene - N,N dimethylamine, followed by adding water to produce
2, 2 - difluoro N,N dimethyl acetamide;
/zb)
treating the 2, 2 - difluoro N,N dimethyl acetamide of step (a) with a mineral
acid having predetermined range of pKa value at an elevated temperature to
form an acetamide-acid complex with a fluoride content in a range of 500 ppm
to 100 ppm;
c) Adding an alcohol at an elevated temperature range and under reflux
condition to achieve ethyl 2, 2 difluoro acetate followed by distillation for
recovering dimethylamine.
2. The single pot process of claim 1, wherein the pKa value of the mineral acid is in a
range of 3.14 to less than <1, preferably in a range of 0.8 to 0.1.
3. The single pot process of claim 1, wherein the elevated temperature is step (b) in a
rangeof50°Cto150°C.
4. The single pot process of claim 1, wherein the mineral acid is selected from a group
of hydrochloric acid, hydrofluoric acid, chloric acid, perchloric acid, nitric acid and
sulfuric acid.
5. The single pot process of claim 2, wherein the mineral acid is preferably sulfuric
acid.
6. The single pot process of claim 1, wherein the alcohol in step (c) is a C1-C4 alcohol,
preferably ethanol.
7. The single pot process of claiml, wherein the temperature in step (c) is in a range of
40°C to 120°C under inert conditions.