The present invention concerns a process for the production of a
fluorinated carboxylic halide having a reduced content of impurities, a fraction of
the fluorinated carboxylic halide having a reduced content of impurities, and its
use in the manufacture of agriculturally and pharmaceutically active compounds
or their intermediates.
Trifluoroacetylchloride (TFAC), difluoroacetylchloride (DFAC) or
chlorodifluoroacetylchloride (CDFAC), are valuable intermediates in chemical
synthesis, for example in the preparation of herbicides, surfactants and
pharmaceuticals. For example, trifluoroacetyl chloride is a starting material for
the synthesis of 4-ethoxy- 1,1,1 -trifluoromethyl-3 -buten-2-one, which can
suitably be converted into cyclic intermediates for agriculturally active
ingredients, see, for example WO201 1/3860 and WO2010037688. CDFAC can,
for example, be converted to fluorosubstituted-3-oxo-alcanoic acids, which can
further be converted into intermediates for agriculturally active compounds, see
for example WO2010037688 and WO2012/25469. DFAC is, for example, used
for the synthesis of CDK inhibitors, as described in WO2006/64251, or
agriculturally active compounds, as described, for example, in WO2005/42468.
CN103524325 describes the purification of a fraction containing 1,1-
difluoroacetyl chloride by compression distillation.
In particular, for industrial manufacture of building blocks for
agriculturally and pharmaceutically active compounds, the purity of fluorinated
carboxylic acid halides is critical for the quality of downstream products,
viability of apparatus, in particular in view of corrosive impurities, and waste
management. There is an ongoing industrial need for a scalable process for the
purification of fluorinated carboxylic halides.
In consequence, the invention concerns a process for producing a
compound of the formula (I) R1-C(0)X having a reduced content of impurities,
wherein Rl is CF2H, CF3 or CC1F2 and X is a halogen, which comprises a)
subjecting a crude fraction comprising compound of formula (I) R1-C(0)X and
impurities to at least two distillation steps, wherein the at least two distillation
steps are performed at different temperatures and b) recovering at least a fraction
of the compound of the formula (I) having a significantly reduced content of
impurities. The invention further concerns a fraction of a compound of formula
(I) R1-C(0)X having a reduced content of impurities, obtainable by the said
distillation process, in particular when the compound of formula (I) was
manufactured by oxidation of a compound of formula (II) Rl-CHX'2, and the
use of the fraction having a reduced content of impurities for the manufacture of
a pharmaceutically or agriculturally active compounds or their intermediates.
Another aspect of the present invention is a process for the manufacture of
agriculturally or pharmaceutically active compounds, comprising the process for
the production of a compound of the formula (I) R1-C(0)X having a reduced
content of impurities.
It has been found that a compound of the formula (I) R1-C(0)X, in
particular CDFAC, having a reduced content of impurities can advantageously
be obtained by applying a distillation process comprising at least two, preferably
at least three distillation steps at different temperatures. The process makes it
possible to achieve an efficient separation of impurities from the compound of
formula (I) R1-C(0)X, in particular CDFAC, by a physical method. The
recovered purified fraction of (I) R1-C(0)X can be used as starting material for
the lab scale industrial scale synthesis and manufacture of further compounds
and building blocks, in particular for agriculturally or pharmaceutically active
compounds, while having a reduced amount of impurities, which allows for
reduced corrosion in apparatus and a reduced amount of impurities and waste in
downstream processes. The process effectively reduces both inorganic, for
example hydrogen halides, and organic impurities. Especially if phosgene is
present, the purification process also allows for the waste management of said
phosgene as a fraction phosgene and often the compound of formula (I) Rl-
C(0)X by recycling said fraction into the process by which the crude fraction
containing the compound of the formula (I) R1-C(0)X is obtained, in particular
if said process is the oxychlorination of alkanes or olefins. The process according
to the present invention can be carried out in an easy manner and allows for use
of distillation apparatus made or partially made or coated or partially coated with
glass or enamel.
In the process according to the present invention, Rl is CC1F2, CF2H or
CF3, wherein CC1F2 is preferred. X is selected from the group consisting of CI, F
and Br, wherein CI is preferred. Most preferably, the compound of formula (I) is
chlorodifluoro-acetyl chloride (CDFAC), wherein Rl is CC1F2 and X is
chlorine.
Acid halides used in the present invention can be obtained, for example, by
photooxidation of halogenated precursor alkanes, in particular as described
in US 5,569,782 the content of which is incorporated by reference in the present
application. In particular, chlorodifluoro acetyl chloride, which is a particularly
preferred compound of formula (I) in the present invention, can be obtained by
photooxidation of l-chloro-l,l-difluoro-2,2-dichloroethane (R 122). Other ways
to manufacture acid halides of formula (I) are described, for example, in
EP0623577, US5545298A, US4643851, US5241 113, US5659078, US6255524
and US7754927. Generally, the purification method according to the present
invention is suitable for reducing impurities in crude fractions containing a
compound of formula (I) and impurities, regardless of the way how the
compound according to formula (I) was produced. The manufacture of the
fraction containing the compound of formula (I) and impurities by oxidation of
formula (II) Rl-CHX'2, wherein Rl has the same definition as above, and X' is
the same or different, wherein X' is a halogen selected from the group consisting
of CI, F and Br, in particular wherein X' is CI, is particularly preferred in view of
the effectiveness of the purification process according to the present invention.
According to the present invention, a crude fraction comprising the
compound of formula (I) R1-C(0)X, in particular CDFAC, and impurities is
subjected to at least two, preferably three distillation steps which are performed
at different temperatures. When two distillation steps are applied, these consist
of a high temperature distillation step and a low temperature distillation step. In
a preferred embodiment, a) comprises at least three distillation steps, which
consist of a high temperature distillation step, a medium temperature distillation
step and a low temperature distillation step. According to a preferred
embodiment, the low temperature distillation step is performed first, the medium
temperature distillation step is performed second and the high temperature
distillation step is performed third. Generally, the at least two, preferably least
three distillation steps can be performed in an order which is suited for the
impurity profile of the crude fraction in order to obtain a fraction containing
compound (I) and a reduced amount of impurities. Preferably, the fraction of the
compound of formula (I), in particular CDFAC, having a reduced content of
impurities is recovered from the high temperature distillation step as bottom
product.
In the present description, any reference to the temperature corresponds to
the temperature measured at the top of the distillation column, also indicated as
"head temperature". The temperature of the bottom of the distillation is adjusted
accordingly.
In a preferred embodiment, at least three distillation steps are applied in a).
Preferably, the at least three distillation steps consist of a low temperature
distillation step, a medium temperature distillation step and a high temperature
distillation step.Concerning the temperature values which are applied in the
different distillation steps, the medium temperature distillation step is generally
carried out at a pressure of at least 0.5 °C lower than the high temperature
distillation step. Generally, the pressure difference between the high temperature
distillation step and the medium temperature distillation step is from 0.5 to 15
°C. Often, the temperature difference between the high temperature distillation
step and the medium temperature distillation step is equal to or more than 1 °C,
preferably equal to or more than 2 °C and most preferably equal to or more than
3 °C. Often, the temperature difference between the high temperature distillation
step and the medium temperature distillation step is equal to or less than 15°C,
preferably equal to or less than 14°C and most preferably equal to or less than
13°C. Generally, the low temperature distillation step is generally carried out at
a pressure of at least 0.5 °C lower than the medium temperature distillation step.
Generally, the pressure difference between the low temperature distillation step
and the medium temperature distillation step is from 0.5 to 15 °C. Often, the
temperature difference between the low temperature distillation step and the
medium temperature distillation step is equal to or more than 1 °C, preferably
equal to or more than 2 °C and most preferably equal to or more than 3 °C.
Often, the temperature difference between the low temperature distillation step
and the medium temperature distillation step is equal to or less than 15°C,
preferably equal to or less than 14°C and most preferably equal to or less than
13°C. Generally, the medium temperature distillation step is carried out at a
head temperature of at least 5°C lower than the high temperature distillation step,
and the low temperature distillation step carried out at a head temperature of at
least 5°C lower than the medium temperature distillation step.
When three distillation steps are applied in a), generally, the temperature in
the high temperature distillation step is from -8 to 8 °C. Often, the temperature
in the high temperature distillation step is equal to or more than -5 °C, preferably
equal to or more than -3 °C and most preferably equal to or more than - 1 °C.
Often, the temperature in the high temperature distillation step is equal to or
lower than 5°C, preferably equal to or lower than 3 °C and most preferably equal
to or lower than 1 °C.
When three distillation steps are applied in a), generally, the temperature in
the medium temperature distillation step is from -18 to -2 °C. Often, the
temperature in the medium temperature distillation step is equal to or more than -
15 °C, preferably equal to or more than -13 °C and most preferably equal to or
more than - 11 °C. Often, the temperature in the high temperature distillation
step is equal to or lower than -5 °C, preferably equal to or lower than -7 °C and
most preferably equal to or lower than -8 °C.
When three distillation steps are applied in a), generally the temperature in
the low temperature distillation step is from -28 to -12 °C. Often, the
temperature in the low temperature distillation step is equal to or more than -25
°C, preferably equal to or more than -23 °C and most preferably equal to or more
than -21 °C. Often, the temperature in the low temperature distillation step is
equal to or lower than -15 °C, preferably equal to or lower than -17 °C and most
preferably equal to or lower than -19 °C.
The fraction of the compound of formula (I) having a reduced content of
impurities is preferably recovered from the high temperature distillation step as
bottom product.
In a preferred embodiment, the compound of formula (I) is CDFAC, and
the distillation is carried out in a first, low temperature distillation step at a
temperature from -22 to -18°C, then in a second, medium temperature distillation
step at a temperature from -12 to -8°C and then in a third, high temperature
distillation step at a temperature from -2 to 2°C. This is particularly preferred if
the crude fraction containing CDFAC and impurities, which is fed to the
distillation process, was obtained by photooxidation of l-chloro-l,l-difluoro-
2,2-dichloroethane (R122). In this embodiment, the fraction A obtained at the
distillation top of the first, low temperature distillation step comprises COF2,
HC1 and C12 and is often fed into a scrubber system. In another aspect, this
fraction A may further be used as crude product for other processes. The bottom
fraction, often comprising CDFAC, CF2C1-CHC12 (R 122), COC12 and
l,ldifluorotetrachloroethane (R 112a), of this first, low temperature, distillation
step is fed to the medium temperature distillation step. The fraction B obtained at
the distillation column top of the second, medium temperature distillation step
comprises COC12 and CDFAC and is fed to the third, high temperature
distillation step. The bottom fraction of the second, medium temperature
distillation step often comprises CF2C1-CHC12 (R 122) and
l,ldifluorotetrachloroethane (R 112a) and can be recycled to the process by
which the crude fraction containing the compound of formula (I) was obtained,
or can further be used as crude product for other processes. The fraction C
obtained at the distillation column top of the third, high temperature distillation
step comprises COC12 and a low content of CDFAC. Fraction C can preferably
be fed into the process to the process by which the crude fraction containing the
compound of formula (I) was obtained, in particular if said process is a
photooxidation process. The COC12 contained in fraction C there is suitably
oxidized to C02, thus handling and waste management of the hazardous COC12
is avoided. CDFAC contained in fraction C advantageously accumulates in
further distillation steps. The bottom fraction of the third distillation step is
recovered as CDFAC having a reduced content of impurities, preferably as fluid.
Preferably, the process for the production of a compound of the formula (I)
R1-C(0)X having a reduced content of impurities is carried out at a pressure of
0.7 to 1.3 bar. Preferably, the process is carried out at ambient pressure, ambient
pressure denoting the pressure which is given by the natural conditions of the
environment of the distillation apparatus. Often, the pressure is about 1 bar.
Generally, it is possible to feed the fractions to be distilled to the
distillation column at any location of the distillation column, be it at the top, the
bottom, or anywhere between the bottom and the top. Often, it is preferred to
feed the fraction to be distilled to the distillation column at a location of at least
20% of the theoretical plates, measured from the bottom of the column, more
preferably at a location of at least 30% of the theoretical plates, measured from
the bottom of the column, and even more preferably at a location of at least 40%
theoretical plates, measured from the bottom of the column. A most preferred
location is of at least 50% of the theoretical plates, measured from the bottom of
the column.
The distillation columns which can be used in the process according to the
invention are known per se. Most preferred are columns made of or partially
made of or coated with or partially coated with glass or enamel. Often, the
columns are conventional plate columns or plate columns of dual-flow type or
alternatively of columns with bulk or structured packing. Glass or enamel
packing is preferred.
In one embodiment of the present invention, the crude fraction of the
compound of formula (I) has been obtained by an oxidation process starting from
a compound of formula (II) R1-CHX' 2, wherein X' is the same or different,
wherein X' is a halogen selected from the group consisting of CI, F and Br, in
particular wherein X' is CI, and wherein Rl has the same definition as above. In
one preferred aspect of this embodiment, the oxidation process is a
photooxidation process in the presence of oxygen, in particular wherein said
photooxidation is further carried out in the presence of added elemental chlorine.
A photooxidation according to this embodiment is particularly advantageous
when a Hg high-pressure lamp doped with a metal iodide is used as a source for
the activating radiation, in particular wherein the metal iodide is selected from
the group consisting of gallium iodide, thallium iodide or cadmium iodide.
Details of such a process are described in EP0638539A, in particular with
respect to the oxidation process by which the crude fraction CDFAC is obtained
from CF2C1-CHC12 (R 122), which is incorporated hereby in its entirety.
Generally, the process for producing a compound of the formula (I)
R1-C(0)X, in particular CDFAC, having a reduced content of impurities can be
carried out batch-wise or continuous. In a batch-wise process, the process can be
carried out in a distillation apparatus which comprises one or more distillation
columns, wherein one distillation column is preferred. In a continuous process,
the process can be carried out in a distillation apparatus which comprises two or
more distillation columns, wherein three or more distillation column are
preferred; three distillation columns are most preferred. The continuous process
is preferred.
In one aspect of the present invention, a fraction comprising the compound
of formula (I), in particular CDFAC, and at least one impurity, in particular
COCl2, is recovered from the high temperature distillation step as top product,
and wherein the fraction comprising the compound of formula (I) and at least
one impurity is fed into a previous process step of the process for the
manufacture of the crude fraction of the compound of formula (I) which is fed to
the process for the production of a compound of the formula (I) R1-C(0)X
having a reduced content of impurities. As described above, the COC12
contained in the fraction obtained as top product from a third, high temperature
distillation step, also denoted as fraction C, there is often suitably oxidized to
C02, thus handling and waste management of the hazardous COCl2 is avoided.
CDFAC contained in fraction C advantageously accumulates in further
distillation steps.
It was found that in the process according to the present invention, a
purified fraction of the compound of formula (I) can suitably be obtained by an
industrially applicable distillation process by applying at least two preferably
three distillation steps at different tempeatures. The process not only allows for
efficient separation and recovery of fractions that a purified and/or can suitably
be disposed of and/or recyled. The process also allows for a distillation
procedure under ambient pressure, which is unexpected as the state of the art
describes compressed distillation procedures or non-industrial distillation
procedures not employing at least two steps, in which the advantageous results
cannot be obtained, or where compression distillation has to be applied, which is
less benificial economically and may also yield less advantageous chemical
results.
The invention further concerns a fraction of a compound of formula (I) Rl-
C(0)X, in particular CDFAC, having a reduced content of impurities, obtainable
by the process according to the present invention. This is particularly preferred if
fraction of CDFAC having a reduced content of impurities was obtained by three
distillation steps of different temperature as described above. In another
embodiment, the invention concerns the use of the fraction as described above
for the manufacture of agriculturally or pharmaceutically active compounds or
intermediates of agriculturally or pharmaceutically active compounds. Such use
is described, for example, in WO201 1/3860, WO2010037688, WO2010037688,
WO2012/25469, WO2006/64251and WO2005/42468, which are all incorporated
by reference in their entirety.
The invention further concerns a process for the manufacture of
agriculturally or pharmaceutically active compounds or intermediates of
agriculturally or pharmaceutically active compounds, comprising the distillation
process according to the present invention and optionally one or more further
process steps to convert the intermediates of agriculturally or pharmaceutically
active compounds into agriculturally or pharmaceutically active compounds.
Such processes are described, for example, in WO201 1/3860, WO2010037688,
WO2010037688, WO2012/25469, WO2006/64251 and WO2005/42468, which
are all incorporated by reference in their entirety.
In a very preferred embodiment according to the present invention, the
crude fraction of the compound of the formula (I) R1-C(0)X, wherein (I) is
CDFAC, is obtained by photooxidation of l-chloro-l,l-difluoro-2,2-
dichloroethane (R 122) in the presence of 0 2 and Cl2. Preferably, the photo
source is a Hg high pressure lamp, which often has 1 kw. Preferably, a glass
photoreactor is held at a temperature of from 75°C to 95°C, preferably of from
80°C to 88°C. 0 2 and Cl2 are fed to a premixer. R 122 is pre-heated in a
vaporizer to a temperature of from 70°C to 120°C, preferably of from 72°C to
78°C, and fed to the premixer. The premixer contents are then injected to the
photoreactor. The molar ratio of 0 2, in relation to R-122, preferably is from 0.35
to 0.5, in particular 0.39 to 0.45. The molar ratio of Cl2, in relation to R-122,
preferably is from 0.08 to 013, in particular 0.1 to 0.13.
Should the disclosure of any patents, patent applications, and publications
which are incorporated herein by reference conflict with the description of the
present application to the extent that it may render a term unclear, the present
description shall take precedence.
The following examples, are intended to explain the invention further
without the intent to limit it.
Example 1: Manufacture of CDFAC
A Duran 50 photoreactor (volume 6 liter) was heated to 85°C, and
irradiated with a 1 kw Hg high pressure lamp. 0 2 was fed to a premixer at a rate
of 113 g/h, and Cl2 was fed to the premixer at a rate of 64 g/h. l-chloro-1,1-
difluoro-2,2-dichloroethane (R 122) was heated is a vaporizer to 74°C, and the
evaporated R 122 was injected to the premixer. The premixer contents were then
injected to the photoreactor. The molar ratio of 0 2 to R 122 was 0.44, the molar
ration of Cl2 to R 122 was 0.1 1. The crude fraction containing CDFAC and
byproducts (mainly COF2, HCl, Cl2, 122, COCl2 and R 122a) was continuously
drawn off the photoreactor and used further in the distillation process.
94.3% of the R 122 was reacted in the process.
The selectivity was 97,06% CDFAC, 1,28 % COF2, 1,59% COCl2 and
0.08% R 112a. The reaction was monitored and analyzed by GC (gas
chromatography) and GC-MS (gas chromatography - mass spectrometry).
The photooxidation is operated continuously.
Example 2 : Distillation of CDFAC
The crude fraction containing CDFAC and impurities obtained by example
1 is fed to a first glass distillation column at 1 bar, which is operated at a head
temperature of -20°C. A fraction containing mainly COF2, HC1 and Cl2 is
withdrawn at the top of the column and fed to a scrubber. The bottom fraction of
the first distillation column is fed to a second glass distillation column at 1 bar,
which is operated at a head temperature of -10°C. The bottom product of the
second distillation column is a fraction containing mainly R 122 and R 112a and
is fed to recycling processes. The top product of the second distillation column is
fed to a third glass distillation column at 1 bar, which is operated at a head
temperature of 0°C. A fraction containing mainly COCl2 and CDFAC is
withdrawn at the top of the column and fed the pre-mixer or the photoreactor of
example 1, where the COCl2 is further oxidized to C0 2, and the CDFAC is
accumulated in downstream distillation steps. The bottom fraction of the third,
high temperature (0°C) distillation step is a CDFAC fraction of 99% purity by
GC. The distillation is operated continuously.

C L A I M S
1. A process for the production of a compound of the formula (I)
R1-C(0)X having a reduced content of impurities, wherein Rl is CF2H, CF3 or
CC1F2 and X is a halogen, which comprises a) subjecting a crude fraction
comprising compound of formula (I) R1-C(0)X and impurities to at least two
distillation steps, wherein the at least two distillation steps are performed at
different temperatures and b) recovering at least a fraction of the compound of
the formula (I) having a reduced content of impurities.
2. Process according to claim 1, wherein Rl is CC1F2 and X is chlorine.
3. Process according to claim 1 or 2, wherein a) comprises at least three
distillation steps, which consist of a low temperature distillation step, a medium
temperature distillation step and a high temperature distillation step.
4. Process according to claim 3, where in the medium temperature
distillation step is carried out at a head temperature of at least 5°C lower than the
high temperature distillation step, and the low temperature distillation step
carried out at a head temperature of at least 5°C lower than the medium
temperature distillation step.
5 . Process according to claim 3 or 4, wherein the head temperature
difference between the high temperature distillation step and the medium
temperature distillation step is from 0.5 to 15°C, wherein the head temperature
difference between the medium temperature distillation step and the low
temperature distillation step is from 0.5 to 15°C.
6. Process according to any one of claims 3 to 4, wherein the low
temperature distillation step is performed first, the medium temperature
distillation step is performed second and the high temperature distillation step is
performed third.
7. Process according to any one of claims 3 to 6, wherein the fraction of
the compound of formula (I) having a reduced content of impurities is recovered
from the high temperature distillation step as bottom product.
8. Process according to any one of claims 1 to 7, wherein the process for
the production of a compound of the formula (I) R1-C(0)X having a reduced
content of impurities is carried out at a pressure of from 0.7 to 1.3 bar.
9. Process according to any one of claims 1 to 8, further comprising a
process wherein the crude fraction of the compound of formula (I) is obtained by
an oxidation process starting from a compound of formula (II) R1-CHX' 2,
wherein X' is the same or different, wherein X' is a halogen selected from the
group consisting of CI, F and Br, in particular wherein X' is CI, and wherein Rl
has the same definition as above.
10. Process according to any one of claims 3 to 9, wherein a fraction
comprising the compound of formula (I) and at least one impurity is recovered
from the high temperature distillation step as top product, and wherein the
fraction comprising the compound of formula (I) and at least one impurity is fed
into a previous process step of the process for the manufacture of the crude
fraction of the compound of formula (I) which is fed to the process for the
production of a compound of the formula (I) R1-C(0)X having a reduced content
of impurities.
11. Process according to any one of claims 1 to 10, wherein the process
for the production of a compound of the formula (I) R1-C(0)X having a reduced
content of impurities is carried out in a distillation apparatus made or partially
made or coated with or partially coated with glass or enamel.
12. Process according to any one of claims 1 to 11, wherein the process
for the production of a compound of the formula (I) R1-C(0)X having a reduced
content of impurities is carried out as a continuous process.
13. A fraction of a compound of formula (I) R1-C(0)X having a reduced
content of impurities, obtainable by the process according to any one of claims 1
to 12.
14. A process for the manufacture of agriculturally or pharmaceutically
active compounds or intermediates of agriculturally or pharmaceutically active
compounds, comprising the process according to any one of claims 1 to 13, and
optionally one or more further process steps to convert the intermediates of
agriculturally or pharmaceutically active compounds into agriculturally or
pharmaceutically active compounds.
15. Use of the fraction according to claim 13 for the manufacture of
agriculturally or pharmaceutically active compounds or intermediates of
agriculturally or pharmaceutically active compounds.