Process for the manufacture of alkenones
This application claims priority to European application No. 12181334.9,
the whole content of this application being incorporated herein by reference for
all purposes.
The present invention relates to a process for the manufacture of
alkenones.
Halogenated alkenones, such as 4-ethoxy-l,l,l-trifluoro-3-buten-2-one
(ETFBO), are building blocks in chemical synthesis, as disclosed, for example,
in U.S. Pat. No. 5,708,175. They may be prepared by reacting an acid chloride
with a vinyl ether as described in the aforementioned patent, or by reacting an
acid anhydride with a vinyl ether.
WO 201 1/003860 describes a process comprising a thermolysis of a
halogenated precursor of an alkenone. Since the process is carried out in absence
of an acid scavenger hydrogen halide is generated in gaseous form and has to be
removed from the reaction mixture during or after the reaction e.g. by heating or
vacuum.
The present invention now makes available an improved process for the
preparation of alkenones, in particular for the preparation of 4-ethoxy- 1,1,1 -
trifluoro-3-buten-2-one (ETFBO).
The process according to the invention allows for a reduction in size of the
equipment used in the preparation of the alkenones.
The process according to the invention also allows for a reduction of
residence time of the reaction mixture in the reactor or reactors.
The process according to the invention further allows for particularly high
selectivity, including configuration isomer selectivity, to the desired alkenone, in
particular ETFBO, under productive conditions. The high selectivity allows
further for simplified purification and high isolated yield of the target product.
The invention relates to a process for the manufacture of an alkenone
comprising the steps of :
(a) providing a halogenated precursor of the alkenone and
(b) subjecting at least a fraction of the halogenated precursor of step (a) to a
thermolysis reaction to form a reaction mixture comprising the alkenone and
a hydrogen halide wherein the hydrogen halide is removed from the reaction
mixture by cyclonic separation.
The term "cyclonic separation" as used herein is intended to denote
methods known in the art of separating a gas from a liquid using rotational
effects and gravity, including for example centrifugal separation techniques. The
cyclonic separation according to the present invention can be performed in a
cyclone separator comprising an inlet, for example a tangential inlet, through
which the reaction mixture is introduced into a cylindrical cyclone barrel, which
may comprise a conical section. Introduction into the barrel imparts a spinning
flow pattern to the reaction mixture. The spinning flow pattern may comprise
circular, helical, or vortical motion, preferably helical motion. Centrifugal force
separates the gaseous components, in particular hydrogen halide, from the liquid
components of the reaction mixture. The gaseous components may leave the
cyclone barrel through a gas outlet, advantageously an axial gas outlet on the top
of the cyclone barrel. The liquid components first travel to the walls of the
cyclone barrel and then down along the conical section to a liquid outlet,
advantageously in the form of an axial liquid outlet on the bottom of the cyclone
barrel. Thus, the gaseous and the liquid components of the reaction mixture are
advantageously withdrawn at opposite sides of the cyclone separator.
In a preferred aspect of the invention the process further comprises the
steps of (c) transferring the at least a fraction of the reaction mixture from
step (b) into a separate reactor, and (d) subjecting the transferred reaction
mixture comprising unreacted halogenated precursor to a thermolysis reaction to
form further alkenone and hydrogen halide. Advantageously, in this preferred
aspect of the invention a fraction of equal to or more than 10 % of the hydrogen
halide is eliminated from the halogenated precursor of step (a) in step (b),
preferably a fraction of equal to or more than 25 % of the hydrogen halide is
eliminated from the halogenated precursor of step (a) in step (b), more preferably
a fraction of equal to or more than 50 % of the hydrogen halide is eliminated
from the halogenated precursor of step (a) in step (b).
In a further preferred aspect of the invention the process comprises a
thermolysis reaction in step (b) and/or in step (d) which is a flash thermolysis
reaction.
For the purpose of the present invention, the term "flash thermolysis"
refers to a process wherein the liquid reaction mixture is heated up in a short
time, preferably less than 20 min, more preferably less than about 15 min.
Generally, the heating time is greater than 1 s, often greater than 15 s .
"Heating time" is understood to denote the time required to heat the liquid
fraction containing the halogenated precursor, in particular a liquid reaction
mixture, from an initial temperature to the temperature of the thermolysis
treatment. A typical initial temperature in step (b) is less than 50°C, often less
than 40°C, preferably equal to or less than 30°C. In one aspect, the initial
temperature is from 15 to 30°C. The initial temperature is generally at
least -50°C, often equal to or greater than -40°C, preferably equal to or greater
than -30°C. Often, the initial temperature in step (b) corresponds to the
temperature of the reaction mixture of step (a) after completion of step (a). A
typical initial temperature in step (d) is less than 120°C, often less than 100°C,
preferably equal to or less than 90°C. In one aspect, the initial temperature is
from 70 to 90°C. The initial temperature is generally at least 20°C, often equal
to or greater than 40°C, preferably equal to or greater than 50°C. Often, the
initial temperature in step (d) corresponds to the temperature of the reaction
mixture of step (c) after completion of step (c).
In step (d), a thermolysis treatment carried out at a temperature of
from 90°C to 120°C, in particular from 95 to 105°C is particularly preferred. In
step (b), a thermolysis treatment carried out at a temperature of from 60°C
to 90°C, in particular from 75 to 85°C is particularly preferred. It has been found
that the aforementioned temperature ranges are particularly efficient, in
particular for the thermolysis of 4-chloro-4-ethoxy-l,l,l-trifluoro-butane-3-one
(CETFBO) to 4-ethoxy-l,l,l-trifluoro-3-butan-2-one (ETFBO) under
elimination of hydrogen chloride. Thus, in a preferred embodiment of the
process of the present invention step (b) carried out at a temperature equal to or
more than 10°C lower than the temperature of step (d).
The thermolysis or flash thermolysis may be carried out under vacuum. In
that case, the pressure in the reactor is often from 100 to 600 mbar, preferably
from 100 mbar to 500 mbar, for example from 200 to 450 mbar. The
thermolysis or flash thermolysis can be optionally carried out under stripping
with an inert gas stream such as nitrogen gas or argon gas. For the purpose of
the present invention, the term "stripping" denotes in particular a physical
separation process where one or more components, in particular a hydrogen
halide, are removed from the liquid reaction mixture by means of a gas stream.
The liquid and gas streams can have concurrent or counter-current flow
directions.
In a preferred embodiment step (a) according to the present is performed in
a first reactor and step (b) is performed in a second reactor.
The term "reactor" as used herein is intended to denote a vessel designed to
contain chemical reactions. The vessel can for example be a tank reactor,
particularly a continuous stirred tank reactor, or a tubular reactor.
The reactor of step (a) is often a tank reactor, preferably a continuously
stirred tank reactor. The reactor of step (d) can be, for example, a distillation
column.
In a more preferred embodiment, step (b) of the present invention is carried
out in a tubular reactor comprising a heating segment. Advantageously, the
tubular reactor constitutes part of the piping connecting two reactors such as the
piping connecting the reactors of step (a) and step (d). Heating in the heating
segment can be carried out by suitable means such as heating the walls of the
tubular reactor. Heating can also be solely or in combination with other suitable
means carried out by providing a hot gas, in particular a hot inert gas such as in
particular nitrogen to the reaction mixture in the heating segment.
The process according to the invention can be performed batch-wise or in a
continuous manner. In a preferred embodiment of the invention the process is
performed continuously.
In a further preferred embodiment of the invention the halogenated
precursor of the alkenone corresponds to Formula (I) :
R1-C(0)-CH 2-CH(X)-OR 2 (I) wherein X represents fluorine, chlorine or bromine
and R1 represents an alkyl group which is optionally substituted by at least one
halogen atom or R1represents CF3C(0)CH 2 ; and R2 represents aryl, substituted
aryl, or an alkyl group which is optionally substituted by at least one halogen
atom. Thus, the process according to the invention can advantageously be
applied to the preparation of an alkenone corresponding to the
formula (0 ) (H) (H)- . In a more preferred aspect of this
embodiment R1 is a fluorinated C1-C4 alkyl group, even more preferably
a CHF2, CC1CF2, or a CF3 group, most preferably a CF3 group. In another
preferred aspect R2 is a C1-C4 alkyl group, preferably a methyl or an ethyl
group. Particularly, the alkenone the process according to the invention is
applied to the preparation of 4-ethoxy- 1,1,1 -trifluoro-3-butan-2-one.
The term "alkyl group" is intended to denote saturated hydrocarbon-based
groups, such as, in particular, a C1-C6 alkyl group. By way of example, mention
may be made of methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl
and hexyl.
The term "aryl group" is intended to denote a group which is derived from
an aromatic nucleus such as a C6-C10 aromatic nucleus, in particular a phenyl or
naphthyl nucleus.
The hydrogen halide removed from the reaction mixture can be for
example hydrogen bromide, hydrogen chloride or hydrogen fluoride. In a
preferred embodiment of the invention the hydrogen halide is hydrogen chloride.
Step (a) of the process according to the invention comprises providing a
halogenated precursor of the alkenone. This can be carried out for example by
filling or pumping the halogenated precursor into a reactor. The halogenated
precursor may be supplied for example by transportation of previously produced
halogenated precursor in a suitable tank. However, it is preferably provided by
reaction of starting compounds which themselves are suitable precursors of the
halogenated precursor such as acid chlorides or acid anhydrides and vinyl ether.
Advantageous embodiments in particular for manufacture of 4-chloro-4-
ethoxy-l,l,l-trifluoro-butane-3-one (CETFBO) from ethyl vinylether (EVE) and
trifluoroacetylchloride (TFAC) are selected from (1) carrying out the reaction in
a reaction mixture containing carboxylic acid halide, (2) carrying out the reaction
in a reaction mixture using alkenone and/or halogenated precursor as solvent, (3)
carrying out the reaction under conditions allowing to avoid or minimize hot
spots, in particular by carrying out the reaction in a turbulent state, (4) carrying
out the reaction in the absence of an acid scavenger for hydrogen halide and
combinations of these embodiments. These embodiments are explained in
further detail in WO 2010/000871, WO 201 1/003854, WO 201 1/003856
and WO 2004/108647, respectively, the contents of which is incorporated by
reference into the present patent application.
Another preferred embodiment of the invention is a process comprising at
least one further step (e) comprising conversion of the alkenone to a heterocyclic
compound wherein the hydrogen halide formed in step (b) and/or step (d) is used
in step (e). Preferably, the heterocyclic compound is a CF3-pyridine derivative
or a CF3-pyrazole derivative.
The term "hydrogen halide formed in step (b) and/or step (d) is used in
step (e)" as used in this embodiment is intended to denote use of the hydrogen
halide for example as a catalyst for the conversion of the alkenone to the
heterocyclic compound in step (e) or use of the hydrogen halide for the
formation of a hydrogen halide salt of any component of the reaction mixture of
step (e), particularly for the formation of a hydrogen chloride salt of the
CF3-pyridine derivative of step (e).
It has been found that the process of the present invention allows for a
reduction in size of the reactors used for the manufacture of the alkenone. The
reduction in reactor size provides the possibility of a reduced residence time,
i.e. the time the reaction mixture spends in the reactor from entering to exiting it.
It has been found that side reactions are dramatically reduced using the process
of the present invention as compared to the processes of the prior art. One side
reaction is the Hetero-Diels- Alder reaction of two molecules of the alkenone,
especially when ETFBO is prepared.
Another side reaction is the addition of the hydrogen halide to the alkenone
leading to the formation of the halogenated precursor and/or to the formation of
oligomers and polymers of the alkenone. It has been found that the addition of
hydrogen halide to the alkenone, i.e. the reversal of the reaction of step (b), is
minimised using the process of the present invention.
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.
Examples :
Continuous preparation of 4-ethoxy-l,l,l-trifluoro-3-buten-2-one :
Pure 4-ethoxy- 1,1,1 -trifluoro-3-buten-2-one (ETFBO), obtained by a
previous synthesis, is placed in the flow part of a recirculation system and cooled
using a chiller. This recirculation system comprises a 20 L flask, 2 one meter
distillation columns filled with 10 mm glass Raschig rings placed on top of
another distillation column, a circulation pump (1500 1/h), 3 tube reactors each
with 3 m path length (diameter 1.5 cm). Once the desired temperature is reached
in the recirculation system, gaseous or liquid trifluoroacetylchloride (15 kg/h ;
113.2 mo1/h) is introduced into the turbulent circulation in front of the first 3 m
reactor and then a small molar excess of ethyl vinyl ether (TFAC/EVE = 1:1.01)
is added after the first 3 m reactor. The level of reaction mixture in the 20L flask
of the recycle apparatus is kept constant by pumping material using a membrane
pump into a pipe connected to a cyclone separator. The pipe is heated by means
of a heating mantle to a temperature of 80°C. The hydrogen chloride formed in
this step is removed from the reaction mixture through the gas outlet of the
cyclone separator. The liquid material is transferred through liquid outlet of the
cyclonic separator and further pumped into an reactor for the second thermolysis
of 4-chloro-4-ethoxy- 1,1,1 -trifluoro-3-butan-2-one (CETFBO) to 4-ethoxy- 1,1,1-
trifluoro-3-buten-2-one (ETFBO). The apparatus comprises a 100 L Pfaudler
ceramic vessel operated at a temperature of 100°C with 3 one meter distillation
columns filled with 10 mm glass Raschig rings and a cooler with removal. The
further conversion of CETFBO to ETFBO under loss of hydrogen chloride takes
place through continuous feeding of the liquid reaction mixture from the cyclone
in the distillation columns. The crude product thus obtained can optionally be
further purified by fine distillation.
C L A I M S
1. A process for the manufacture of an alkenone comprising the
following steps :
(a) providing a halogenated precursor of the alkenone and
(b) subjecting at least a fraction of the halogenated precursor of step (a) to a
thermolysis reaction to form a reaction mixture comprising the alkenone and
a hydrogen halide wherein the hydrogen halide is removed from the reaction
mixture by cyclonic separation.
2. The process of claim 1 further comprising the steps of
(c) transferring at least a fraction of the reaction mixture from step (b) into a
separate reactor, and
(d) subjecting the transferred reaction mixture comprising unreacted
halogenated precursor to a thermolysis reaction to form further alkenone and
hydrogen halide.
3. The process of claim 2 wherein a fraction of equal to or more
than 10 % of the hydrogen halide is eliminated from the halogenated precursor of
step (a) in step (b), preferably a fraction of equal to or more than 25 % of the
hydrogen halide is eliminated from the halogenated precursor of step (a) in
step (b), more preferably a fraction of equal to or more than 50 % of the
hydrogen halide is eliminated from the halogenated precursor of step (a) in
step (b).
4. The process of any of the claims 1 to 3 wherein the thermolysis
reaction in step (b) and/or in step (d) is a flash thermolysis reaction.
5. The process of any of the claims 2 to 4 wherein step (b) is carried out
at a temperature equal to or more than 10 °C lower than the temperature of
step (d).
6. The process of any of the claims 1 to 5 wherein step (a) is performed
in a first reactor and step (b) is performed in a second reactor.
7. The process of claim 6 wherein the reactor in step (b) is a tubular
reactor comprising a heating segment.
8. The process of any of the claims 1 to 7 wherein the process is
performed continuously.
9. The process of any of the claims 1 to 8, wherein the halogenated
precursor of the alkenone corresponds to Formula (I) :
R1-C(0)-CH 2-CH(X)-OR 2 (I) wherein X represents fluorine, chlorine or bromine
and R1 represents an alkyl group which is optionally substituted by at least one
halogen atom or R1 represents CF3C(0)CH 2 ; and R2 represents aryl, substituted
aryl, or an alkyl group which is optionally substituted by at least one halogen
atom.
10. The process of claim 9, wherein R1 is a fluorinated C1-C4 alkyl group,
preferably a CHF2, CC1CF2, or a CF3 group, more preferably a CF3 group.
11. The process of claim 9 or 10, wherein R2 is a C1-C4 alkyl group,
preferably a methyl or an ethyl group.
12. The process of any of the claims 1 to 11 wherein the alkenone is
4-ethoxy- 1,1,1 -trifluoro-3-butan-2-one.
13. The process of any of the claims 1 to 12 wherein the hydrogen halide
is hydrogen chloride.
14. The process according to any of claims 1 to 13 comprising at least one
further step (e) comprising conversion of the alkenone to a heterocyclic
compound wherein the hydrogen halide formed in step (b) and/or step (d) is used
in step (e).
15. The process according to claim 14 wherein the heterocyclic compound
is a CF3-pyridine derivative or a CF3-pyrazole derivative.