U.S. patent application number 11/605604 was filed with the patent office on 2007-06-21 for process for preparing beta-keto nitriles and salts thereof.
This patent application is currently assigned to Wacker Chemie AG. Invention is credited to Klas Sorger, Jurgen Stohrer.
Application Number | 20070142661 11/605604 |
Document ID | / |
Family ID | 37508322 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070142661 |
Kind Code |
A1 |
Sorger; Klas ; et
al. |
June 21, 2007 |
Process for preparing beta-keto nitriles and salts thereof
Abstract
A process for preparing .beta.-keto nitrites or salts thereof is
provided by reacting a nitrile with a carboxylic ester in the
presence of an alkali metal alkoxide or alkaline earth metal
alkoxide. Alcohol formed as a by-product is distilled off. The
volume of alcohol distilled off is continually replaced by metering
in an essentially equal volume of nitrile. The nitrile is provided
in excess based on the carboxylic ester to be converted.
Inventors: |
Sorger; Klas; (Munchen,
DE) ; Stohrer; Jurgen; (Pullach, DE) |
Correspondence
Address: |
BROOKS KUSHMAN P.C.
1000 TOWN CENTER
TWENTY-SECOND FLOOR
SOUTHFIELD
MI
48075
US
|
Assignee: |
Wacker Chemie AG
Munich
DE
|
Family ID: |
37508322 |
Appl. No.: |
11/605604 |
Filed: |
November 29, 2006 |
Current U.S.
Class: |
558/352 |
Current CPC
Class: |
C08F 2/20 20130101 |
Class at
Publication: |
558/352 |
International
Class: |
C07C 253/22 20060101
C07C253/22 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 17, 2005 |
DE |
10 2005 054 904.7 |
Claims
1. In a process for preparing .beta.-keto nitrites of the general
formula (1a) or salts thereof of the general formula (1b) ##STR3##
by reacting a nitrile of the general formula (2)
R.sup.2--CH.sub.2--C.ident.N (2) with carboxylic esters of the
general formula (3) ##STR4## in the presence of an alkali metal
alkoxide or alkaline earth metal alkoxide, wherein: R.sup.1 is a
linear or branched, saturated or unsaturated, nonaromatic, aromatic
or heteroaromatic C.sub.1-C.sub.30-hydrocarbon radical which is
cyclic or contains cyclic groups and is optionally substituted by
Q; R.sup.2 is hydrogen or a linear or branched alkyl radical; Q is
selected from the group comprising halogen, amino, hydroxyl, cyano,
nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl,
heteroaryl; and M is an alkali metal or alkaline earth metal ion, R
is a C.sub.1-C.sub.10-alkyl radical, the improvement comprising: a)
distilling off the alcohol R--OH formed as a by-product, optionally
in the form of an azeotrope; b) continually replacing the volume
distilled off with an essentially equal volume of additional
nitrile by such that overall the nitrile is provided in excess
based on the carboxylic ester to be converted.
2. The process of claim 1, wherein the carboxylic ester, the
nitrile and the alkali metal or alkaline earth metal alkoxide are
initially charged into a reaction vessel in essentially equimolar
amounts.
3. The process of claim 1, wherein the ratio of total nitrile added
to carboxylic ester is from 4 to 6:1.
4. The process of claim 1, wherein the continual further metered
addition of the nitrile is effected continuously or in
portions.
5. The process of claim 1, wherein the alkali metal alkoxide used
is sodium methoxide or sodium ethoxide.
6. The process of claim 1, wherein the nitrile is selected from the
group comprising acetonitrile, propionitrile and butyronitrile.
7. The process of claim 1, wherein the carboxylic esters are
selected from the group comprising optionally Q-substituted and
optionally enantiomerically enriched or enantiomerically pure
alpha-, beta- or gamma-amino acid esters or alpha-, beta- or
gamma-hydroxy acid esters.
8. The process of claim 1, wherein the reaction is effected at a
temperature from 70 to 120.degree. C.
9. The process of claim 1, wherein the reaction is performed in the
presence of an inert solvent.
10. The process of claim 1, wherein the reaction is performed
without addition of additional inert solvents.
11. The process of claim 1, wherein the ratio of total nitrile
added to carboxylic ester is from 2 to 10:1.
12. The process of claim 1, wherein the ratio of total nitrile
added to carboxylic ester is from 3 to 7:1.
13. In a process for preparing .beta.-keto nitrites of the general
formula (1a) or salts thereof of the general formula (1b) ##STR5##
by reacting a nitrile of the general formula (2)
R.sup.2--CH.sub.2--C.ident.N (2) with carboxylic esters of the
general formula (3) ##STR6## in the presence of an alkali metal
alkoxide or alkaline earth metal alkoxide, wherein: R.sup.1 is a
linear or branched, saturated or unsaturated, nonaromatic, aromatic
or heteroaromatic C.sub.1-C.sub.30-hydrocarbon radical which is
cyclic or contains cyclic groups and is optionally substituted by
Q; R.sup.2 is hydrogen or a linear or branched alkyl radical; Q is
selected from the group comprising halogen, amino, hydroxyl, cyano,
nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl,
heteroaryl; and M is an alkali metal or alkaline earth metal ion, R
is a C.sub.1-C.sub.10-alkyl radical, the improvement comprising: a)
distilling off the alcohol R--OH formed as a by-product, optionally
in the form of an azeotrope; b) continually replacing the volume
distilled off with an essentially equal volume of additional
nitrile by such that overall the nitrile is provided in excess
based on the carboxylic ester to be converted, wherein the ratio of
total nitrile added to carboxylic ester is from 4 to 6:1.
14. The process of claim 13, wherein the continual further metered
addition of the nitrile is effected continuously or in
portions.
15. The process of claim 13, wherein the alkali metal alkoxide used
is sodium methoxide or sodium ethoxide.
16. The process of claim 13, wherein the nitrile is selected from
the group comprising acetonitrile, propionitrile and
butyronitrile.
17. The process of claim 13, wherein the carboxylic esters are
selected from the group comprising optionally Q-substituted and
optionally enantiomerically enriched or enantiomerically pure
alpha-, beta- or gamma-amino acid esters or alpha-, beta- or
gamma-hydroxy acid esters.
18. The process of claim 13, wherein the reaction is performed in
the presence of an inert solvent.
19. In a process for preparing .beta.-keto nitriles of the general
formula (1a) or salts thereof of the general formula (1b) ##STR7##
by reacting a nitrile of the general formula (2)
R.sup.2--CH.sub.2--C.ident.N (2) with carboxylic esters of the
general formula (3) ##STR8## in the presence of an alkali metal
alkoxide or alkaline earth metal alkoxide, wherein: R.sup.1 is a
linear or branched, saturated or unsaturated, nonaromatic, aromatic
or heteroaromatic C.sub.1-C.sub.30-hydrocarbon radical which is
cyclic or contains cyclic groups and is optionally substituted by
Q; R.sup.2 is methyl; Q is selected from the group comprising
halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio,
acyl, silyl, silyloxy, aryl, heteroaryl; and M is an alkali metal
or alkaline earth metal ion, R is a C.sub.1-C.sub.10-alkyl radical,
the improvement comprising: a) distilling off the alcohol R--OH
formed as a by-product, optionally in the form of an azeotrope; b)
continually replacing the volume distilled off with an essentially
equal volume of additional nitrile by such that overall the nitrile
is provided in excess based on the carboxylic ester to be
converted, wherein the ratio of total nitrile added to carboxylic
ester is from 4 to 6:1.
20. The process of claim 13, wherein the carboxylic esters are
selected from the group comprising optionally Q-substituted and
optionally enantiomerically enriched or enantiomerically pure
alpha-, beta- or gamma-amino acid esters or alpha-, beta- or
gamma-hydroxy acid esters.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to a process for preparing .beta.-keto
nitrites and salts thereof.
[0003] 2. Background Art
[0004] .beta.-Keto nitrites and salts thereof are important
synthesis units for the preparation of active pharmaceutical
ingredients and crop protection compositions.
[0005] E. H. Kroeker et al., J. Am. Chem. Soc., 1934, 56, p. 1171
discloses the preparation of 3-keto-4-methylvaleronitrile by
reacting ethyl isobutyrate with acetonitrile in stoichiometric
ratio in the presence of sodium ethoxide. In this reaction, sodium
ethoxide is initially charged into a reactor with three one third
portions of a 1:1 mixture of carboxylic ester and acetonitrile
added. Excess nitrile is not used in this process. In each case,
after addition of the ester-acetonitrile mixture, the alcohol
formed as a by-product is distilled off. The yield of this
preparation is only 44% of theory.
[0006] J. B. Dorsch et al., J. Am. Chem. Soc., 1932, 54, p. 2960
also discloses a process for preparing .alpha.-benzoalkyl cyanides,
in which ester and alkoxide are initially charged in equimolar
amounts into a reactor. A 25% excess of nitrile is then metered in.
After the nitrile has been fully metered in, the alcohol formed is
distilled off. In this process, only a 60% yield of the theoretical
yield is obtained.
[0007] EP 220220 B1 describes the reaction of carboxylic esters
with an excess of acetonitrile in the presence of the base sodium
methoxide. The equilibrium is sifted to the product side by the use
of excess acetonitrile and by the distillative removal of the
alcohol formed in the reaction together with acetonitrile. In this
process, a yield of .beta.-keto nitrile sodium salt of 83% of
theory can be achieved. However, this process has the disadvantage
that a very large excess of from 13 to 14 equivalents of
acetonitrile based on the carboxylic ester is employed. The
majority of acetonitrile of greater than 12 equivalents is lost in
the distillative removal of the alcohol. In addition, the high
acetonitrile excess leads to a high total volume of the reaction
mixture and hence to low concentrations and poor space-time yields.
These disadvantages make the process uneconomical for industrial
scale applications.
[0008] EP 1316546 A1 discloses a process in which acetonitrile is
reacted with an excess of carboxylic ester in the presence of the
base sodium methoxide. The equilibrium of the reaction is shifted
to the product side by an excess of carboxylic ester and
distillative removal of methanol formed together with acetonitrile
The present process provides yields up to 82 to 86% of theory based
on the conversion of acetonitrile. However, the process has the
disadvantage that a majority of the carboxylic ester used in excess
is lost in the workup, which makes the process uneconomical,
especially for the conversion of valuable and hence expensive
carboxylic ester substrates. In addition, the entire amount of
carboxylic ester is initially charged in the process. This leads to
a high total volume and hence to low concentrations and moderate
space-time yields. For this reason too, the process is not
economical for the industrial scale.
[0009] In the processes disclosed by EP 220220 B1 and EP 1316546
A1, excess acetonitrile and excess carboxylic ester serve
simultaneously as a solvent that keeps the reaction mixture or the
suspension which forms in a readily stirrable form and prevents the
viscosity of the reaction mixture from increasing slurrying).
[0010] DE 10143858 A1 discloses the reaction of acetonitrile with
diethyl oxalate and sodium methoxide in the presence of the
tert-butyl methyl ether solvent under specific reaction conditions.
In the process, acetonitrile is used only in a very small excess of
not more than 15% based on the oxalic diester. The methanol which
is formed is not distilled off to shift the equilibrium. This
process only achieves a yield of not more than 67% of theory. The
process is optimized especially for using oxalic diesters as the
substrate. Because of the low achievable yields and the low
space-time yields from the use of solvents, the process is not
suitable for the broad industrial preparation of keto nitrites.
[0011] The processes known from the prior art do not provide
satisfactory industrial scale preparation of .beta.-keto nitriles
or salts thereof. In particular, high chemical yields and high
concentrations of the reactants (and hence high space-time
performances) are desirable with large excesses of one reactant
preferably avoided.
SUMMARY OF THE INVENTION
[0012] It is thus an object of the invention to provide an
alternative process for preparing .beta.-keto nitrites or salts
thereof. It is a particular object of the invention to provide a
process which is suitable for industrial use enabling high chemical
yields of .beta.-keto nitriles or salts thereof while working with
high space-time yields and avoiding large excesses of acetonitrile
or carboxylic ester.
[0013] An object of the invention is achieved by a novel process in
which by-products formed are removed from the reaction system and
the volume removed from the reaction system is replaced by metering
in additional nitrile.
[0014] It has been surprisingly found that the preparation of
.beta.-keto nitriles or salts thereof succeeds in a particularly
advantageous and economically viable manner in high space-time
yields when alcohol formed during the reaction is distilled off and
additional acetonitrile added while the alcohol is distilled off.
The additional nitrile is metered in leading to the utilization of
an excess of nitrile based on the ester converted in the overall
assessment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
[0015] The invention provides a process for preparing .beta.-keto
nitrites of the general formula (1a) or salts thereof of the
general formula (1b) ##STR1## wherein R.sup.1 is a linear or
branched, saturated or unsaturated, nonaromatic, aromatic or
heteroaromatic C.sub.1-C.sub.30-hydrocarbon radical which is cyclic
or contains cyclic groups and is optionally substituted by Q;
R.sup.2 is hydrogen or a linear or branched alkyl radical; Q is
selected from the group comprising halogen, amino, hydroxyl, cyano,
nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl,
heteroaryl; M is an alkali metal or alkaline earth metal ion,
[0016] The .beta.-keto nitrites of the general formula (1a) or
salts thereof of the general formula (1b) are formed by reacting a
nitrile of the general formula (2) R.sup.2--CH.sub.2--C.ident.N (2)
wherein R.sup.2 is as defined above with carboxylic esters of the
general formula (3) ##STR2## wherein R.sup.1 is as defined above
and R is a C.sub.1-C.sub.10-alkyl radical, in the presence of an
alkali metal alkoxide or alkaline earth metal alkoxide.
[0017] In this process, the alcohol R--OH formed as a by-product is
distilled off (optionally in the form of an azeotrope) while
continually replacing the distilled off volume with an essentially
equal volume by metering in further nitrile. The nitrile is used in
excess overall based on the carboxylic ester to be converted.
[0018] A feature of the invention is that the amounts of alcohol or
azeotrope distilled off are compensated for in terms of volume by
further metered addition of an excess of nitrile, so that the total
volume of the reaction mixture remains essentially constant over
the course of the reaction. An effect of the inventive procedure is
that the steady-state concentration of the nitrile during the
entire reaction is kept virtually constant, since the volume
distilled off (which comprises essentially alcohol or an azeotrope
of alcohol and nitrile) is continuously replaced by addition of
additional nitrile. In this way, the reaction mixture does not
continuously become depleted in nitrile. However, it is not
necessary to work with large, especially steady-state, excesses of
nitrile which lead to undesired dilution and reduce the space-time
yield.
[0019] The increase in the amount of nitrile alone, i.e. working
with a constant, in some cases also very high, excess of nitrile,
has been found to be negative and does not lead to a significant
shift in equilibrium to the product side.
[0020] An advantage of the process of the invention is that the
excess of nitrile used is significantly less than in the known
prior art processes, while the chemical yield is significantly
higher.
[0021] In variations of the present embodiment, the
C.sub.1-C.sub.30-hydrocarbon radicals R.sup.1 are linear or
branched, saturated or unsaturated alkyl, aryl, heteroaryl, alkenyl
or alkynyl radicals which are cyclic or contain cyclic groups. In
heteroaromatic C.sub.1-C.sub.30-hydrocarbon radicals for R.sup.1,
the heteroatoms can preferably be selected from the group
comprising oxygen, sulfur, nitrogen and phosphorus. The
C.sub.1-C.sub.30-hydrocarbon radicals for R.sup.1 may optionally be
substituted by Q, wherein Q is preferably be selected from the
group comprising F, Cl, Br, I, CN, NO.sub.2, OH, carbonyl,
C.sub.1-C.sub.10-alkoxy, aralkyloxy, C.sub.1-C.sub.6-trialkylsilyl,
C.sub.1-C.sub.6-trialkylsilyloxy, NH.sub.2,
C.sub.1-C.sub.10-alkylamino, di-C.sub.1-C.sub.10-alkylamino,
C.sub.1-C.sub.6-trialkylsilylamino,
C.sub.1-C.sub.6-trialkylsilyl-C.sub.1-C.sub.10-alkylamino,
tert-butyloxycarbonylamino, benzyloxycarbonylamino, aryl, aralkyl,
alkaryl, aralkenyl, alkenylaryl or heteroaryl radicals. The latter
groups may in turn be substituted by radicals selected from the
group of F, Cl, Br, I, CN, NH.sub.2, NO.sub.2,
C.sub.1-C.sub.10-alkoxy radicals, C.sub.1-C.sub.10-alkylamino
radicals or C.sub.1-C.sub.10-alkyl radicals.
[0022] Preferred unsaturated, aromatic and heteroaromatic radicals
for R.sup.1 are selected from the group comprising allyl, vinyl,
furyl, pyrrolyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl,
piperazinyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl,
morpholinyl, thiazolyl, isothiazolyl, indolyl, triazinyl, thienyl,
thiophenyl, phenyl, and naphthyl. These groups may in turn be
substituted by radicals selected from the group comprising methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
trifluoromethyl, methoxy, ethoxy, phenoxy, benzyloxy, amino,
N-methylamino, N,N-dimethylamino, N-benzyl, N,N-dibenzyl,
N-phthalimido, cyano, nitro, hydroxyl, fluorine, chlorine, and
bromine.
[0023] Preferred saturated radicals for R.sup.1 are linear or
branched alkyl radicals which are cyclic or contain cyclic groups
and are optionally substituted by Q. More preferably, R.sup.1 is an
alkyl radical selected from the group comprising methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,
n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
[0024] Preferred carboxylic esters of the general formula (3)
include aliphatic, aromatic or heteroaromatic carboxylic esters in
which the R.sup.1 radicals are optionally substituted by Q, alpha-,
beta- or gamma-amino acid esters and alpha-, beta- or gamma-hydroxy
acid esters. Preferably, these compounds are in enantiomerically
enriched or enantiomerically pure form wherein the R.sup.1 radicals
are each a saturated or unsaturated organic radical that is
substituted by an amino or hydroxyl group and optionally by Q. The
amino or hydroxyl groups in the alpha-, beta- or gamma-amino acid
esters and alpha-, beta- or gamma-hydroxy acid esters may also be
substituted or protected.
[0025] More preferably, Q is fluorine, chlorine, bromine, nitro,
cyano, carbonyl, hydroxyl, amino, N-methylamino, N,N-dimethylamino,
N-benzyl, N,N-dibenzyl, N-acetylamino, N-acetyl-N-methylamino,
tert-butyloxycarbonylamino, N-benzyloxycarbonylamino, methoxy,
ethoxy, tert-butyloxy, phenoxy, benzyloxy, acetyl, propionyl,
pivalinoyl, phenyl, naphthyl, benzyl, furyl, piperidinyl,
pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, imidazolyl,
pyrimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl,
isothiazolyl, indolyl, triazinyl, thienyl or thiophenyl. These
groups are optionally substituted by radicals selected from the
group comprising methyl, ethyl, n-propyl, isopropyl, butyl,
sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, allyl, vinyl, phenyl, furyl, piperidinyl, pyrrolidinyl,
quinolinyl, pyridyl, piperazinyl, imidazolyl, pyrimidinyl,
oxazolyl, isoxazolyl, morpholinyl, thiazolyl, isothiazolyl,
indolyl, triazinyl, thienyl, thiophenyl, fluorine, chlorine,
bromine, nitro, cyano, amino, hydroxy, methoxy, ethoxy, phenoxy,
trimethylsilyl, triethylsilyl, acetyl, propionyl, amino,
N,N-dimethylamino, N-benzyl, N-acetylamino, N-acetyl-N-methylamino
or N-benzyloxycarbonylamino, and also acetyl-, amino-,
N-methylamino-, N,N-dimethylamino-, N-benzyl-, N-acetylamino-,
N-acetyl-N-methylamino-, N-benzyloxycarbonylamino-, nitro-,
methyl-, ethyl-, propyl-, isopropyl-, butyl-, sec-butyl-,
tert-butyl-, methoxy-, ethoxy-, phenoxy-, acetoxy-, benzyloxy-,
trimethylsilyl-, trimethylsilyloxy, triethylsilyloxy-, fluoro-,
chloro-, bromo-, iodo- and cyanophenyl or -naphthyl.
[0026] Preferred radicals for R.sup.2 are hydrogen and
C.sub.1-C.sub.10-alkyl radicals, especially methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; in this
context especially methyl, ethyl, n-propyl and isopropyl.
[0027] More preferably, nitriles of the general formula (2) are
selected from the group comprising acetonitrile, propionitrile and
butyronitrile, especially acetonitrile.
[0028] In the esters of the general formula (2), the
C.sub.1-C.sub.10-alkyl radicals R are preferably selected from the
group comprising methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, especially methyl, ethyl, n-propyl and
isopropyl.
[0029] Suitable alkoxides include alkali metal alkoxides and
alkaline earth metal alkoxides. Preferably, the alkoxides are metal
alkoxides, especially the methoxides, ethoxides, propoxides,
butoxides and pentoxides of sodium and potassium. More preferably,
the alkoxides are selected from sodium methoxide and sodium
ethoxide. The alkoxide is used in solid form or as a solution in
alcohol or other suitable solvents. Preferably, the alkoxide is in
solid form, which has an advantageous effect on the space-time
yields.
[0030] The alkoxides are used in a ratio of from 0.5 to 2:1,
preferably from 0.7 to 1.5:1. More preferably, the alkoxides are
used in a ratio from 0.9 to 1.1:1, based on the carboxylic ester.
Most preferably, the ratio is such that the stoichiometric
(equimolar) amounts of alkoxide and carboxylic ester are used.
[0031] The nitrile, especially acetonitrile, is used in excess
overall based on the carboxylic ester. In one variation, the ratio
of nitrile to carboxylic ester to be converted is from 2 to 10:1.
Preferably, the ratio of nitrile to carboxylic ester to be
converted is from 3 to 7:1. More preferably, the ratio of nitrile
to carboxylic ester to be converted is from 4 to 6:1.
[0032] In another embodiment of a process of the invention, 0.3 to
2 equivalents of nitrile, (especially acetonitrile) based on
carboxylic ester, are initially charged together with carboxylic
ester and alkoxide into a reaction vessel. Preferably, 0.5 to 1.5
equivalents of nitrile, (especially acetonitrile) based on
carboxylic ester, are initially charged together with carboxylic
ester and alkoxide into a reaction vessel. More preferably, 0.9 to
1.1 equivalents of nitrile, (especially acetonitrile) based on
carboxylic ester, are initially charged together with carboxylic
ester and alkoxide into a reaction vessel. In this way, a very high
concentration of the mixture is achieved. The sequence of mixing of
nitrile, carboxylic ester and alkoxide may be as desired.
Preferably alkoxide is added first followed by addition of nitrile
and carboxylic ester. It is also possible to first add alkoxide and
carboxylic ester and then nitrile, (optionally at elevated
temperature). The reaction is effected at elevated temperature
between 50 and 150.degree. C. Preferably, the temperature is from
70 to 120.degree. C.
[0033] Alcohol is formed as the reaction progresses. To shift the
equilibrium, the alcohol formed in the course of the reaction, or
the azeotropic mixture of alcohol and nitrile is distilled
continually out of the reaction mixture. The azeotropic mixture in
this scenario regularly forms depending on the selection of the
nitrile especially when acetonitrile is used. In the case of a
low-boiling carboxylic ester, the azeotropic mixture may include
alcohol, nitrile and carboxylic ester, The alcohol formed is
regularly distilled off as an azeotrope together with the
acetonitrile with additional acetonitrile continually added during
the reaction, either continuously or in portions. This methodology
may also be used for other nitrites.
[0034] The volume of alcohol or azeotrope distilled off (e.g.,
especially of the alcohol-acetonitrile mixture) corresponds
approximately to the volume of additional nitrile added.
Accordingly, the reaction takes place at maximum concentration,
which leads to very high space-time yields.
[0035] The nitrile (e.g., acetonitrile) is added generally in a
ratio from 0.5 to 9:1 based on carboxylic ester. Preferably, this
ratio is from 1 to 6:1. More preferably, this ratio is from 2 to
5:1.
[0036] In a variation of the process of the present invention,
generally a 2- to 10-fold excess of nitrile is used. Preferably a
3- to 7-fold excess of nitrile is used. More preferably, a 4- to
6-fold excess of nitrile is used. These amounts are particularly
useful when the nitrile is acetonitrile.
[0037] Contrary to the prior art processes, it has been
surprisingly found that the addition of nitrile during the
distillative removal of the alcohol formed or azeotrope thereof
with the nitrile allows a high, especially steady-state, excess of
acetonitrile (for example from 12 to 13 equivalents in the process
known from EP 220022 B1) based on carboxylic ester to be avoided.
The processes of the present invention allow high chemical yields
of >85-90% of theory with virtually complete conversion based on
the carboxylic ester. Surprisingly, for this purpose, a total of
only, 3 to 6 equivalents of nitrile are added during the reaction.
Preferably, a total of only 2 to 5 equivalents are added during the
reaction. The continual metered addition of nitrile during the
distillative removal of alcohol has a surprisingly advantageous
influence on the reaction.
[0038] In a particularly preferred embodiment of the process of the
present invention, the entire amount of carboxylic ester and
alkoxide to be converted is initially charged with a portion of the
total amount of nitrile (preferably in a stoichiometric (equimolar)
ratio) used which has an advantageous effect on the reaction time,
the space-time yield and the profile of the entire reaction. For
example, when a suspension of one equivalent of sodium methoxide,
one equivalent of methyl cyclopropanecarboxylate and one equivalent
of acetonitrile is heated to 90.degree. C. for 1 hour, a clear
solution is surprisingly formed in spite of the high concentration
of reactants and absence of additional solvent. Addition of further
acetonitrile to this solution allows methanol or a mixture of
methanol and acetonitrile to be distilled off in a technically
simple manner without slurrying with the equilibrium of the
reaction shifted to the product side (cf. Example 1a). It is
surprising that at temperatures of more than 70.degree. C., a clear
homogeneous, highly mobile solution forms after a short reaction
time, without any need to add solvents such as polar aprotic
solvents (e.g., excess acetonitrile), or ethers such as
tetrahydrofuran or methyl tert-butyl ether.
[0039] A high excess of acetonitrile or carboxylic ester, which
serves as a solvent to prevent slurrying in the known processes, is
thus not required. When, in contrast, as described in E. H. Kroeker
et al., J. Am. Chem. Soc., 1934, 56, p. 1171, excess alkoxide based
on stoichiometric amounts of carboxylic ester and acetonitrile is
initially charged, a slurrylike suspension which is difficult to
stir is formed in the course of heating, and tends to form crusts
on the vessel walls and conglutinate. This has a disadvantageous
effect on reaction times, yields and purities of the products
prepared leading to problems, especially in industrial scale
implementation.
[0040] In contrast, in the process according to the invention, a
stoichiometric mixture of alkoxide, nitrile and ester without
solvent is heated and further nitrile added continually during the
distillative removal of alcohol-nitrile mixture such that virtually
full conversion based on ester proceeds within surprisingly very
short reaction times. For example, consider a mixture of one
equivalent of sodium methoxide, one equivalent of methyl
cyclopropanecarboxylate, and a total of 4.5 equivalents of
acetonitrile (of which initially only one equivalent has been
initially charged together with the other reactants) heated to
90.degree. C. The methanol-acetonitrile azeotrope which forms is
distilled off and an amount of acetonitrile essentially identical
to the volume is added continuously with the methyl
cyclopropanecarboxylate being fully converted after only 3.5 hours.
In contrast thereto, in the process known from E. H. Kroeker et
al., J. Am. Chem. Soc., 1934, 56, p. 1171, stoichiometric amounts
of acetonitrile, sodium ethoxide and ethyl isobutyrate are used
with only 44% of the keto nitrile being obtained after 9 hours at
from 115 to 120.degree. C.
[0041] It is additionally surprising that, when the reaction in the
process according to the invention is performed, only very small
losses as a result of cocondensation of carboxylic ester or
nitrile, especially acetonitrile, occur. When, in contrast, the
addition of the nitrile to the mixture of ester and alkoxide is
dispensed with, especially for esters of aliphatic carboxylic
acids, the undesired formation of condensation products of the
ester caused by base-catalyzed cocondensation is observed in the
course of heating of the mixture of ester and alkoxide. Such
condensation products can surprisingly be avoided almost entirely
by the process according to the invention.
[0042] As a result of the small steady-state excess of acetonitrile
in the reaction mixture, which is inherent to the process according
to the invention, undesired cocondensation products of the
acetonitrile are also formed only in a minimal fraction. The
metered addition of acetonitrile to a clear stoichiometric mixture
of sodium methoxide, carboxylic ester and acetonitrile with
simultaneous distillative removal of methanol-acetonitrile mixture
has a particularly advantageous effect on the minimization of
cocondensation products of the acetonitrile and polymerization of
acetonitrile.
[0043] In contrast to EP 220220, considerably more fractions of
undesired by-products are formed when a mixture of one part of
methyl caproate and 13 parts of acetonitrile is heated to reflux,
some of the methanolic sodium methoxide solution is metered in and
a mixture of methanol and acetonitrile is distilled off at the same
time. This result from the self-addition or -condensation of the
acetonitrile present in high excess in the presence of the
base.
[0044] In a particularly preferred embodiment of the process of the
invention, a stoichiometric mixture of alkoxide, nitrile and
carboxylic ester is initially charged to a reaction vessel without
additional solvent. The mixture is heated with additional nitrile
metered in continuously as alcohol or alcohol-nitrile mixture is
distillatively removed. until virtually full conversion based on
carboxylic ester has been attained. Subsequently, residues of
alcohol and nitrile are distilled off as far as possible,
optionally after addition of an inert solvent. The keto nitrile
salt which forms initially is filtered off, or, alternatively, the
mixture is worked up under aqueous conditions to release the keto
nitrile. In this way, particularly high product yields and purities
can be achieved within short reaction times of from 3 to 6 hours at
maximum concentration and particularly high space-time yields, and
hence in a very economically viable reaction overall.
[0045] The inventive reaction of the carboxylic ester with the
nitrile in the presence of an alkoxide can also be carried out in
the presence of an inert solvent. Suitable inert solvents are
ethers (example e.g., tert-butyl methyl ether, dibutyl ether,
dimethoxyethane or diethoxyethane), high-boiling glycols (example
e.g., polyethylene glycols), alcohols (e.g., isopropanol,
n-butanol, 2-butanol or tert-butanol), hydrocarbons (e.g., toluene,
xylene or mesitylene), or polar aprotic solvents (e.g.,
N,N-dimethylformamide, dimethyl sulfoxide or N-methyl-pyrrolidone).
Particularly useful solventions include dibutyl ether,
dimethoxyethane, diethoxyethane, toluene, N,N-dimethylformamide and
dimethyl sulfoxide. Preferably, the solvent is toluene.
[0046] In a particularly preferred embodiment of the process of the
invention, the reaction is, however, performed without addition of
additional inert solvents. This has an advantageous effect on the
space-time yield.
[0047] Toward the end of the reaction, there may be precipitation
of keto nitrile salt of the general formula (1b) formed. In order
to complete the precipitation, it is possible to distill off
residual nitrile, if appropriate together with residues of alcohol
or unconverted ester. The keto nitrile salt can then be isolated by
filtration. Optionally, the filtration can be performed in the
presence of an inert solvent, especially when the mixture is
filtered at temperatures below the reaction temperature, in
particular between 10 and 80.degree. C. Suitable inert solvents are
the abovementioned solvents, especially toluene, dibutyl ether,
tert-butyl methyl ether, dimethoxyethane or diethoxyethane.
[0048] The keto nitrile salts prepared by the process of the
invention are surprisingly of very high purity and can be processed
further directly in most cases. Optionally, the keto nitrile salts
can also be purified further, for example by washing,
recrystallization or extraction. The keto nitrites can be released
in particularly pure form from the purified keto nitrile salts.
[0049] To directly release keto nitrile from the prepared keto
nitrile salt, the mixture is hydrolyzed with water or aqueous acid
upon completion of reaction. The hydrolysis may also be performed
at significantly higher temperatures than room temperature without
noticeable yield. The hydrolysis is effected at temperatures
between 0 and 100.degree. C. Preferably, the hydrolysis is effected
at temperatures from 30 to 80.degree. C. For hydrolysis, water or
aqueous acid, for example hydrochloric acid or sulfuric acid, is
introduced into the reaction mixture until solids dissolve fully.
Alternatively, it is also possible to meter the reaction mixture
into water or aqueous acid. When water is used for the hydrolysis,
keto nitrile salt dissolves in the form of its enolate of the
general formula (1b) in the aqueous alkaline phase. Optionally, the
aqueous phase can be extracted with organic, water-immiscible
solvent. The aqueous phase is then acidified with an acid to pH
from 0 to 8, which releases keto nitrile of the general formula
(1a). Preferably, the aqueous phase is then acidified with an acid
to pH from 2 to 5. When aqueous acid is used directly for the
hydrolysis, keto nitrile is immediately released. The released keto
nitrile is finally extracted with organic, water-immiscible solvent
and optionally purified, for example by filtration, distillation,
crystallization or extraction. It is also possible to perform the
workup and release of keto nitrile by adding a nonaqueous acid, for
example formic acid or acetic acid, or to meter the reaction
mixture into the nonaqueous acid. Released keto nitrile can then be
isolated directly by distillation, filtration or optionally, after
addition of water or of an aqueous acid, by extraction with organic
water-immiscible solvent. The keto nitrile salt is preferably
isolated by filtration, or keto nitrile is released by aqueous
workup.
[0050] The pressure range of the reaction is not critical and can
vary within wide limits. The pressure is typically from 0.01 to 20
bar; the reaction is preferably performed under standard pressure
(atmospheric pressure).
[0051] The reaction is preferably performed with inertization with
an inert protective gas, especially nitrogen or argon. The reaction
can be performed continuously or batchwise.
[0052] All symbols above of the formulae above are each defined
independently of one another.
[0053] In the examples which follow, unless stated otherwise in
each case, all amounts and percentages are based on the weight, all
pressures are 0.10 MPa (abs.) and all temperatures are 20.degree.
C. The examples serve to further illustrate the process according
to the invention and are in no way to be interpreted as a
restriction.
EXAMPLE 1A
Preparation of 3-cyclopropyl-3-ketopropionitrile sodium salt
(Workup by Filtration)
[0054] At room temperature, a four-neck flask with internal
thermometer, dropping funnel, precision glass stirrer and attached
distillation apparatus with separating column under nitrogen
protective gas is initially charged with 21.6 g of solid sodium
methoxide (0.4 mol), and 16.4 g of acetonitrile (0.4 mol) and 40.0
g of methyl cyclopropanecarboxylate (0.04 mol) are metered in. The
suspension is heated to 85.degree. C. and stirred for 1 hour to
form a clear mixture. Subsequently, a mixture of methanol and
acetonitrile is distilled off at an initial top temperature of
63.degree. C. As the distillative removal begins, further
acetonitrile is metered into the reaction mixture (total of 74 g,
1.8 mol), the volume of added acetonitrile corresponding to the
methanol-acetonitrile mixture distilled off. In the course of the
distillative removal, the internal temperature of the reaction
mixture is increased from 90 to 95.degree. C. Toward the end of the
distillative removal of MeOH/acetonitrile, a suspension forms.
Finally, almost pure acetonitrile is distilled off at a top
temperature of 80.degree. C. (composition of the entire distillate
in % by weight by GC: 72.4% acetonitrile, 26% methanol, 1.6% methyl
cyclopropanecarboxylate). Monitoring of conversion (NMR, GC) shows
that the ester is converted apart from 2 mol %. Subsequently, 40 ml
of toluene are added to the reaction mixture and residual
acetonitrile is distilled off (and can be recovered). The mixture
is cooled to 70.degree. C. and filtered through a glass frit. The
filtercake is washed twice with 20 ml each time of acetone and
dried under reduced pressure. 45.1 g of
3-cyclopropyl-3-ketopropionitrile sodium salt of pale yellowish
color are obtained, which corresponds to a yield of 86% of theory
(chem. purity: >95%).
EXAMPLE 1B
Preparation of 3-cyclopropyl-3-ketopropionitrile (Aqueous
Workup)
[0055] Procedure is initially analogous to that in Example 1a. The
toluenic suspension is cooled to 50.degree. C. With cooling, 40 ml
of water are metered in, which forms a clear solution.
Subsequently, the pH is adjusted to 4 with 20% hydrochloric acid.
After phase separation, the aqueous phase is extracted twice with
20 ml each time of methylene chloride. The combined organic phase
is washed with 20 ml of 8% NaHCO.sub.3 solution. After distillative
removal of solvent, 3-cyclopropyl-3-ketopropionitrile of slightly
brownish color is obtained in a yield of 36.2 g (83% of theory,
chem. purity: 98%).
EXAMPLE 2A
Preparation of 4,4-dimethyl-3-ketovaleronitrile sodium salt (Workup
by Filtration)
[0056] In an analogous procedure to Example 1a using 10 g of methyl
pivalate (0.086 mol), 4.65 g of NaOMe (0.086 mol) and 17.7 g of
acetonitrile (0.43 mol), 3.5 g (0.086 mol) are initially charged
into the reaction flask, after filtration, washing and drying, 12.7
g of the sodium salt of 4,4-dimethyl-3-ketovaleronitrile (93% of
theory) are obtained in a purity of 97%.
EXAMPLE 2B
Preparation of 4,4-dimethyl-3-ketovaleronitrile (Aqueous
Workup)
[0057] The procedure of this example is analogous to that in
Example 1a using the amounts of Example 2a. This example results in
9.8 g of 4,4-dimethyl-3-ketovaleronitrile (91% of theory) in a
purity of 98.2% (GC).
EXAMPLE 3
Preparation of 3-ketocapronitrile (Aqueous Workup)
[0058] In an analogous procedure to Example 1b, 10 g of methyl
butyrate (0.098 mol), 5.28 g of NaOMe (0.098 mol) and 4.02 g of
acetonitrile (0.098 mol) are initially charged into the reaction
flask. The mixture is heated to 85.degree. C. After 2 hours, the
distillative removal of a mixture of MeOH and acetonitrile is
commenced, and, as the distillative removal begins, an additional
16.1 g of acetonitrile (0.39 mol) are metered in continuously.
After an additional 2.5 h of distillative removal of
MeOH/acetonitrile and metering in of additional acetonitrile, 20 ml
of toluene are added and residual MeOH/acetonitrile are distilled
off. After cooling to 60.degree. C., 10% hydrochloric acid is added
down to a pH of 3. After phase separation, the aqueous phase is
extracted twice with 20 ml each time of methylene chloride. The
organic phase is washed once with 15 ml of 5% NaHCO.sub.3 solution.
After the toluene and methylene chloride solvents is distilled off,
3-ketocapronitrile is obtained in the form of an almost colorless
liquid in a yield of 8.5 g based on butyric ester converted (89% of
theory, chem. purity: 98.6%). By GC, 12 mol % of methyl butyrate
are lost together with MeOH and acetonitrile distilled off.
EXAMPLE 4
Preparation of 3-phenylpropionitrile (Aqueous Workup)
[0059] In analogous procedure to Example 1b, 10 g of methyl
benzoate (0.074 mol), 4.0 g of NaOMe (0.074 mol) and 3.01 g of
acetonitrile (0.074 mol) are initially charged. The mixture is
heated to 90.degree. C. After 1.5 hours, a clear solution forms,
and the distillative removal of a mixture of MeOH and acetonitrile
is commenced. As the distillative removal begins, an additional
12.4 g of acetonitrile (0.29 mol) are metered in continuously.
After an additional 2.5 hours of distillative removal of
MeOH/acetonitrile and metering in of additional acetonitrile, 20 ml
of toluene are added, and residual MeOH/acetonitrile is distilled
off. After cooling to 40.degree. C., 10% hydrochloric acid is added
down to a pH of 3, which dissolves solids that form. After phase
separation, the aqueous phase is extracted twice with 20 ml each
time of methylene chloride. The organic phase is washed once with
10 ml of 8% NaHCO.sub.3 solution. After the toluene and methylene
chloride solvents is distilled off, 3-phenylpropionitrile is
obtained in the form of an almost colorless solid in a yield of
10.1 g (92% of theory, chem. purity: 97%). After recrystallization
from ethanol, colorless solid having an m.p. of 82.degree. C. is
obtained.
* * * * *