Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Process for preparing glyoxylic esters or their
hydrates
Glyoxylic esters, for example ethyl glyoxylate,
methyl glyoxylate, benzyl glyoxylate or L-(-)-menthyl
glyoxylate, are important reagents in organic
chemistry, since the a,-oxo ester group is a highly
reactive group which can take part in a number of
reactions. L-(-)-Menthyl glyoxylate (MGH) is, for
example, an important C2 building block for asymmetric
synthesis, for chiral acetals, for oxathiolanes, for
stereo-controlled addition reactions to alkenes and
nitroalkanes, or for Grignard reactions.
The preparation of glyoxylic esters from the
corresponding malefic or fumaric diesters by means of a
two-stage ozonolysis and reduction process is already
known from a number of literature references.
Thus, for example, according to J. Org. Chem.
1982, 47, pp. 891-892 ethyl, methyl or benzyl
glyoxylates are obtained by ozonolysis of the
corresponding malefic diesters in dichloromethane,
subsequent reduction of the ozonide by means of
dimethyl sulfide and subsequent distillation.
WO 96/22960 also describes a two-stage process
for preparing menthyl glyoxylate as intermediate for
menthyl dihydroxyacetate, in which dimenthyl maleate or
dimenthyl fumarate is ozonized in the first stage in a
halogenated hydrocarbon or carboxylic ester, preferably
in the presence of a lower aliphatic alcohol, and in
the second stage the resultant ozonolysis product is
either reduced with a dialkyl sulfide or by catalytic
hydrogenation with hydrogen to give menthyl glyoxylate.
The disadvantage with the previously known
processes, however, is that after the ozonolysis step,
peroxide-containing ozonolysis products are present,
which must then be reduced in a second step, either by
means of catalytic hydrogenation or in the presence of
dialkyl sulfides or aryl sulfides, trialkyl phosphides,
to give the corresponding glyoxylic esters.
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To avoid these problems, EP 0 884 232 Al
proposed, for example, preparing MGH via ozonolysis of
malefic acid monomenthyl ester sodium salt as starting
material. Although in this process the previously
necessary reduction step is omitted, the starting
material used is not available on the market and must
therefore be prepared in an additional stage by
reacting malefic anhydride with menthol.
DE 44 35 647 further discloses a process in
which a 50$ strength glyoxylic acid solution is
esterified with an excess of menthol using sulfuric
acid and azeotropic removal of water. The monohydrate
of MGH is isolated from the reaction mixture by forming
a bisulfate adduct and phase separation with subsequent
release from the adduct.
The disadvantage of this process is the complex
isolation, the necessity of very gentle drying of the
product, and the considerable amount of waste.
Tetrahedron Lett. 39, 4223-4226 (1998)
discloses the transesterification of ethyl glyoxylate
diethyl acetal with titanium(IV) ethoxide. However, in
this reaction, first, an expensive starting material is
used, and secondly, the described workup of the
reaction mixture after the reaction mixture has ended,
by hydrolysis of the catalyst and flash chromatography,
is problematic and too expensive for an industrial
scale.
It was therefore an object of the present
invention to find a process for preparing glyoxylic
esters which does not 'have the abovementioned
disadvantages of previously known processes.
The present invention therefore relates to a
process for preparing glyoxylic esters which comprises
a) transesterifying a glyoxylic ester hemiacetal
directly with an alcohol in the presence of a catalyst,
or
b) first converting a glyoxylic ester hemiacetal into
the corresponding glyoxylic ester acetal and then
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transesterifying it with an alcohol in the presence of
a catalyst,
whereupon, following a) and b, the acetal is cleaved to
give the desired free glyoxylic ester or its hydrate.
According to the invention the starting
material used is a glyoxylic ester hemiacetal. Suitable
glyoxylic ester hemiacetals are described, for example,
in EP-P-0 099 981.
Preference is given to glyoxylic acid methyl ester
methyl hemiacetal (GMHA), glyoxylic acid ethyl ester
hemiacetals, glyoxylic acid propyl ester hemiacetals,
glyoxylic acid isopropyl ester hemiacetals, glyoxylic
acid t- or n-butyl ester hemiacetals.
Particularly preferably, GMHA is used as starting
compound.
Glyoxylic esters or their hydrates which are
obtained by the inventive process are compounds whose
ester moiety is derived either from chiral or nonchiral
primary, secondary or tertiary alcohols. Esters of
primary alcohols are preferably derived from ethanol,
butanol, propanol and hexanol. Preferably, esters of
secondary or tertiary alcohols, in particular acyclic,
monocyclic, bicyclic terpene alcohols, or of acyclic,
monocyclic, tricyclic sesquiterpene alcohols, di- or
triterpene alcohols are prepared, which may be
unsubstituted or substituted.
Particularly preferred end products are
glyoxylic esters or their hydrates which are derived
from optionally variously substituted monocyclic or
bicyclic terpene alcohols, for instance from menthols,
phenylmenthol, borneol_, fenchol, etc.
In the inventive process, the hemiacetal can be
transesterified either directly (variant a) to give the
desired glyoxylic ester, or it can first be converted
into the corresponding acetal (variant b), which is
then transesterified in a similar manner to variant a).
The hemiacetal is converted into the
corresponding acetal in a manner known per se by means
of an alcohol and acid catalysis.
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The acetalization is preferably performed using the
alcohol which is already present in the hemiacetal.
However, it is also possible to prepare mixed acetals.
Suitable alcohols are methanol, ethanol, propanol,
butanol, hexanol. Preferably, the hemiacetals are
therefore converted into glyoxylic acid ester dimethyl
acetals, diethyl acetals, etc. Particular preference is
given to glyoxylic acid methyl ester dimethyl acetal.
The corresponding alcohol is used either in the
liquid stage or vapor stage for the acetalization.
Preferably, the acetalization is carried out using
alcohol vapor.
Suitable catalysts are customary acids, such as H2S04,
p-toluenesulfonic acid, acid ion exchangers, etc.
Preferably, HzS04 is used.
The water eliminated is preferably discharged together
with the superheated alcohol vapor and is thus
continuously taken off from the reaction mixture.
The transesterification of the hemiacetals or acetals
is performed in an alcohol as reaction medium.
Preferably, anhydrous alcohols are used.
To obtain the above-described glyoxylic esters,
therefore the alcohol is used which leads to the
desired ester moiety in the end product.
These are accordingly chiral or nonchiral, primary,
secondary or tertiary alcohols, preferably secondary or
tertiary alcohols, in particular acyclic, monocyclic,
bicyclic terpene alcohols, monocyclic or tricyclic,
sesquiterpene alcohols, di- or triterpene alcohols.
Particularly preferred alcohols are therefore again
optionally variously substituted mono- or bicyclic
terpene alcohols, for example menthols, phenylmethols,
borneol, fenchol, etc.
The corresponding alcohol can be used in an
equimolar amount, but also either in excess or in a
deficiency.
Thus, it is preferred, in the case of cheaper alcohols,
to add these in excess to the hemiacetal or acetal,
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whereas in the case of expensive alcohols, for instance
menthol etc., the acetal is used in excess.
In addition to the alcohol used, a further
anhydrous solvent can be used, for instance
unsubstituted or substituted CS-C2oalkanes, for example
hexane and heptane etc., and alkenes, silicon
compounds, for instance silicone oil etc., or other
solvents which are inert under the reaction conditions.
The transesterification takes place according
to the invention in the presence of specific catalysts.
Catalysts which come into consideration are stannic,
titanic or zirconic esters, lithium compounds, and
basic catalysts.
Suitable catalysts, from the group of the tin
catalysts, are dialkyltin dicarboxylates having 1-12
carbon atoms in the alkyl moiety. Dicarboxylate
moieties which come into consideration are diacetates,
dilaurates, maleates, diisooctanates, or mixed
dicarboxylates, in particular with longer-chain fatty
acid esters.
Examples of these are dibutyltin diacetate,
dibutyltin dilaurate, dibutyltin diisooctoate, dibutyl-
tin maleate, dioctyltin dilaurate, etc.
Preferably dibutyltin diacetate, mixed dibutyltin
dicarboxylates with longer-chain fatty esters and
dioctyltin dilaurate are used.
Suitable titanium catalysts are titanium(IV)
ethoxide, isopropoxide, propoxide, butoxide,
isobutoxide, etc. ..
Preferably, titanium(IV) isopropoxide is used.
Suitable catalysts from the group of zirconium
catalysts are zirconates, such as tetrapropyl
zirconate, tetraisopropyl zirconate, tetrabutyl
zirconate, citric acid diethyl ester zirconate, etc.
Lithium catalysts which can be used are lithium salts,
for example chlorides, lithium alkoxides or lithium
hydroxides, but also organic lithium compounds, for
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instance butyllithium. A preferred lithium catalyst is
butyllithium.
However, in particular in the case of variant b), basic
catalysts can also be used, for instance alkali metal
(Na,K) compounds, alkaline earth metal (Mg) compounds
or aluminum compounds. Examples of these are
hydroxides, alkoxides or organometallic compounds.
Preferably, tin catalysts, titanium catalysts
or lithium catalysts are used.
In the direct transesterification of the hemiacetal
according to variant a), preferably dialkyltindi-
carboxylates are added as catalysts.
The amount of catalyst used is 0.001 to
molo, preferably 0.005 to 5 molo, and particularly
15 preferably 0.02 to 3 mol%.
The reaction mixture, in both variant a) and
variant b), is preferably heated to the boiling point
of the reaction mixture, so that the reaction
temperature, depending on the reactants, is between
20 20°C and 200°C. The transesterification can be carried
out further at atmospheric pressure, but also at
reduced pressure or superatmospheric pressure from
0.001 to 200 bar. Preferably, the pressure is between
0.01 and 10 bar, particularly preferably it is
atmospheric pressure. The alcohol eliminated in the
transesterification is preferably distilled off
continuously.
If the alcohol used is a non-anhydrous alcohol,
the reaction mixture is heated before the catalyst is
added, the water is distilled off and only then is the
catalyst added.
Removal of the catalyst after the reaction ended
succeeds in good yield by washing with water,
hydrolyzing the catalyst and filtering the metal oxide
which precipitated out or, preferably by distilling off
the product from the catalyst, preferably on a thin-
film or short-path evaporator. It is also possible, in
particular in the case of removal by distilling off the
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product, to recycle the removed catalyst or the
distillation residue to a new reaction mixture.
Subsequently to the transesterification
reaction, the acetal cleavage is performed to give the
free glyoxylic ester or its hydrate. The acetal
cleavage is carried out by acid catalysis or in the
presence of lanthanide catalysts. Suitable catalysts
for the acid catalysis are acids in which the risk of
hydrolyzing the ester moiety is as low as possible.
Examples of these are HZS04, p-toluenesulfonic acid,
etc., and, in particular for variant b), formic acid,
acetic acid, etc. Lanthanides which come into
consideration are various compounds of cerium,
lanthanum, ytterbium, samarium, etc.
These are, in particular, chlorides, sulfates,
carboxylates.
In the acetal cleavage, the free aldehyde
groups of the glyoxylic ester are formed with
elimination of the corresponding alcohol. The alcohol
is preferably distilled off continuously in this case.
The preferred end product is the hydrate of the
desired glyoxylic ester, so that the free glyoxylic
ester is, if appropriate, converted into the hydrate by
addition of water.
In a particular embodiment, the glyoxylic ester
methyl hemiacetal or acetal is, after trans-
esterification is complete, cleaved by means of formic
acid. In this case, the reaction between the methanol
being eliminated and the formic acid forms methyl
formate and water. The methyl formate is separated off,
and the reaction water forms directly the desired
hydrate of the glyoxylic ester.
In a particularly preferred embodiment, the
acetal of variant a) or b) is heated with formic acid
for a short period, that is to say to the boiling point
in less than one hour, the methyl formate is taken off
and the remaining reaction mixture is rapidly cooled.
This process variant is particularly advantageous in
the preparation of the menthyl ester, since byproduct
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formation, i.e. menthene formation, is avoided.
Residual formic acid is extracted or preferably
distilled off. The remaining reaction mixture is
preferably dissolved in hexane either directly while
still warm or after heating.
The hexane solution is then washed with hot water and
the end product is crystallized out from the organic
phase.
The hexane mother liquor can be recycled and reused for
subsequent isolations without loss of quality to the
end product.
Preferably, the desired end products are prepared by
variant b).
By means of the inventive process, conversion
rates of up to 100 o are achieved, the yields are above
950, while according to the prior art (Tetrahedron),
yields of only up to 80o are achieved. Owing to the
mild transesterification conditions, product purities
of greater than 99.90 up to 1000 can be achieved.
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Example l:
a) Preparation of glyoxylic acid methyl ester dimethyl
acetal
1200 g (10 mol) of glyoxylic acid methyl ester
methyl hemiacetal and 40 g of concentrated sulfuric
acid were heated to 105°C in a distillation apparatus
consisting of a bottom vessel, stirrer, distillation
column (10 plates) and distillation head with reflux
divider. 300 g (9.4 mol) of methanol were pumped per
hour through a spiral of a stainless steel tube which
was thermostated to 110°C in a heating bath. The
methanol vapor exiting at the outlet of the heating
spiral was introduced into the reaction solution using
a submerged tube at the bottom of the bottom-phase
vessel. The reflux divider at the top of the
distillation column was set to a ratio of take-off to
reflux of approximately 10:1, as a result of which
stationary conditions were rapidly established with a
top temperature of approximately 70°C and a bottom
temperature of 105°C. After 6 h the reaction was
complete, the introduction of methanol vapor was
stopped and the heating was shut off. The reaction
mixture was then neutralized with solid sodium hydrogen
carbonate. The apparatus was evacuated and the reaction
mixture fractionally distilled. 1270 g (9.5 mol) of
glyoxylic acid methyl ester dimethyl acetal having a
content of 99.50 (GC) were obtained. The yield based on
glyoxylic acid methyl ester methyl hemiacetal was thus
950. -
b) Transesterification of glyoxylic acid methyl ester
dimethyl acetal to Z-menthyl glyoxylate dimethyl acetal
402 g (3 mol) of glyoxylic acid methyl ester
dimethyl acetal, 312 g (2 mol) of L-menthol and 1 g of
dibutyltin diacetate were heated to 105°C in the
apparatus described in step a). Methanol formed by the
transesterification was taken off continuously at the
top of the column. The reaction was complete after
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15 h. The residual L-menthol content was < O.lo (GC).
The reaction mixture was freed from the catalyst in the
short-path evaporator at 10 mbar, with approximately
15 g of catalyst solution being produced at the bottom
of the short-path evaporator, and 635 g of reaction
mixture in the distillate of the short-path evaporator.
The reaction mixture was then fractionally distilled
under reduced pressure. 130 g (0.97 mol) of a glyoxylic
acid methyl ester dimethyl acetal and 501 g (1.94 mol)
of L-menthyl glyoxylate dimethyl acetal having a
content of 99o were obtained. The yield, based on
glyoxylic acid methyl ester dimethyl acetal was 970 of
theory.
The catalyst solution arising at the bottom of the
short-path evaporator was used in a new operation
instead of the fresh dibutyltin diacetate. After
carrying out the experiment using 402 g of glyoxylic
acid methyl ester dimethyl acetal and 312 g of
L-menthol as specified above, 509 g (1.95 mol) of
L-menthyl glyoxylate dimethyl acetal having a content
of 99o were obtained. The yield, based on glyoxylic
acid methyl ester dimethyl acetal, was therefore 980 of
theory.
c) Acetal cleavage of Z-menthyl glyoxylate dimethyl
acetal to give Z-menthyl glyoxylate monohydrate
100 g (0.39 mol) of L-menthyl glyoxylate
dimethyl acetal and 400 g of formic acid were heated to
boiling for 12 min in the apparatus described in step
a). Methyl formate was taken off at the top of the
column, while formic acid was held in the reaction
system at a bottom temperature of approximately 100°C.
The reaction mixture was then rapidly cooled to room
temperature, the apparatus was evacuated and the formic
acid was taken off. The residue was dissolved in 800 g
of n-hexane by brief heating to boiling temperature.
The hexane solution was washed twice, each time with
400 ml of water at 60°C. The hexane solution was then
cooled, with L-menthyl glyoxylate monohydrate
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crystallizing out. The crystals were filtered off, the
filter cake was washed with 100 g of cold hexane and
dried at room temperature under reduced pressure.
64.6 g (0.28 mol) of L-menthyl glyoxylate monohydrate
having a purity of 99.80 (HPLC) were obtained. The
angle of rotation (aD2o - _74°, c _ 1 g/100 m1, aceto-
nitrile/water 95:5) and the FTIR spectra and
1H-NMR spectra were in correspondence.
The mother liquor and the washing hexane were
combined, concentrated to 800 g and used in a new
operation instead of the fresh n-hexane. After the
experiment was carried out using 100 g of L-menthyl
glyoxylate dimethyl acetal and 400 g of formic acid as
specified above, 86.4 g (0.38 mol) of L-menthyl
glyoxylate monohydrate having a purity of 99.80 (HPLC)
were obtained. The angle of rotation (a2° - -74°,
c = 1 g/100 ml, acetonitrile/water 95:5) and the FTIR
spectra and 1H-NMR spectra were in correspondence. The
yield was therefore 97% of theory.
