The present invention relates to a process for purifying an a-keto ester as claimed in
claim!
Various a-keto esters of the general formula
o 0.
wherein R1 and R2 are as defined below, have already been described in the literature.
In general, these compounds are relatively unstable and show keto/enol tautomerism.
JP-A-2005336120 and JP-A-2005325050 describe the preparation and/or storage of
a-keto esters, whereas the formation of the enol form is to be suppressed.
a-Keto esters are typically prepared by adding a nucleophile to a 1,2-diester. Such
reactions are described, for example, in Creary, J. Org. Chem. 1987, 5026-5030, or in
Rozen et al., J. Org. Chem. 2001, 496-500. Alternatively, a-keto esters can also be
obtained by oxidizing an a-hydroxy ester, for example according to WO 2003/000638.
For the addition of a nucleophile to a 1,2-diester, the nucleophile used may, for
example, be a Grignard reagent or an organolithium compound. In this case, the
a-keto ester is prepared according to the following reaction scheme
o oo
wherein R1 is alkyl; R2, R2" are alkyl or benzyl; and M is Li, MgCI, MgBr or AIR12. An
example of such a process is the preparation of methyl 2-oxobutyrate by reaction of
dimethyl oxalate with ethylmagnesium chloride. Methyl 2-oxobutyrate is an important
building block for the preparation of more complex organic compounds, in particular of
pharmaceutical products.
In such addition reactions, secondary and tertiary alcohols of the formula
R3 OH
O
(III)
are usually formed as by-products, wherein R1 is alkyl, R2 is alkyl or benzyl and R3 is
alkyl or H. These alcoholic by-products are difficult to remove. In particular, on
industrial scale the alcohols cannot be removed by the standard methods being
customary in this field.
This is true in particular for a-keto esters having a low molecular mass which, by virtue
of their relatively low boiling point, would otherwise be highly suitable for distillative
purification. Thus, for example, methyl 2-oxobutyrate cannot be purified by distillation
since it is not possible to remove the alcoholic by-products in this manner.
JP 09 020 723 discloses a process for purifying an a-keto ester. In this process, the
crude product is heated with a strong acid to effect the decomposition of any byproducts
present. This entails the risk that a part of the desired product is decomposed
too, so that a lower yield is obtained.
Therefore, it is an object of the present invention to provide an ecologically and
economically advantageous process for purifying an a-keto ester, which process
allows secondary and tertiary alcohols to be removed and provides high yields of pure
a-keto ester. The process according to the invention should be suitable in particular for
use on an industrial scale.
This object is achieved by a process as claimed in claim 1. The process according to
the invention allows the purification of an a-keto ester of the formula
wherein R1 is a saturated alkyl group with 1-5 carbon atoms, and R2 is a saturated
alkyl group with 1-5 carbon atoms or is a benzyl group. In this process, the alcoholic
by-products resulting from the preparation of the a-keto ester, namely secondary and
3
tertiary alcohols of formula
R3 OH
R'^'V
o
(III).
wherein R1 and R2 are as defined above and R3 is hydrogen or a saturated alkyl group
with 1-5 carbon atoms, are removed. The process according to the invention
comprises the following steps:
(a) treatment of the a-keto ester of formula I, which is to be purified, with a
carboxylic anhydride and an acid, which is essentially insoluble under the
filtration conditions, for esterifying the secondary and tertiary alcohols of
formula III,
(b) filtration of the reaction mixture to remove the acid and
(c) distillation to isolate the purified a-keto ester.
The term "filtration conditions" refers to the external conditions predominating during
the filtration, i.e. during step (b) of the process according to the invention. This relates
in particular to the temperature and the pressure at which the filtration is carried out.
The filtration conditions are furthermore characterized by components present in the
reaction mixture prior to the filtration, in particular any solvents present.
By treatment with the carboxylic anhydride under acidic conditions, the secondary and
tertiary alcohols are converted into the corresponding diester according to the following
reaction scheme
ay0
< OH ° ° H- R> b °
0 ° (IV).
In contrast, the a-keto ester is inert to these reagents and remains unchanged. The
esterification under acidic conditions is advantageous, in particular when tertiary
alcohols are to be removed, since these are relatively inert. The esterification is
preferably carried out at a temperature of 20-100 °C, in particular at 40-80 °C, for
1
example at about 50 °C, and at atmospheric pressure under protective gas.
After esterification, the acid, which is essentially insoluble under the filtration
conditions, is separated off by filtration. This permits a rapid and inexpensive removal
of the acid and supersedes an extraction, which would require the use of solvents, thus
leading to additional costs. Moreover, a filtration is, in particular on an industrial scale,
considerably less complicated than an extraction, and less product is lost. Last but not
least, the acid can be isolated in a simple manner and, if desired, re-used.
Since the boiling points of the a-keto ester and the esterified secondary and tertiary
alcohols, i.e. the corresponding diesters, differ considerably, the different products can
subsequently be separated by distillation, and the a-keto ester can be obtained in pure
form.
The process according to the invention permits a rapid and efficient purification of the
a-keto ester and affords a product having a high degree of purity. The degree of purity
of the a-keto ester obtained in this manner is preferably at least 94%, in particular at
least 97%, ideally at least 98%. The process steps are neither dangerous nor
complicated and are inexpensive.
In a preferred embodiment, the acid which is essentially insoluble under the filtration
conditions is a solid at the filtration temperature. The term "filtration temperature" refers
to the temperature at which the reaction mixture is filtered. For example, acidic
polysilicates are employed as acids. Suitable acidic polysilicates are, for example,
amorphous polysilicates of the allophane type; chain polysilicates of the hormite type,
such as, for example,
polygorskite;
two-layer polysilicates of the kaolin type, such as, for example,
kaolinite (AI2(OH)4[Si205]), and
halloysite (Al2(OH)4[Si205] x 2 H20);
three-layer polysilicates of the smectite type, such as, for example,
sauconite (Nao.3Zn3(Si,AI)4Oio(OH)2 x 4 H2O),
saponite ((Ca2,Na)o.3(Mg,Fe2+)3 (Si,AI)4Oio(OH)2 x 4 H20),
montmorillonite (M+o.3(AI,Mg)2Si40io(OH)2 x n H2O), wherein M+ in natural
montmorillonite denotes one or more of the cations Na+, K+, Mg2+ and Ca2+,
vermiculite ((Mg,Fe2+,AI)3(AI,Si)4Oio(OH)2 x 4 H20),
nontronite (Nao.3Fe2
3+ (Si,AI)4Oio(OH)2 x 4 H20), and
hectorite(Nao.3(Mg,Li)3Si4Oio(F,OH)2);
5
three-layer polysilicates of the illite type; and
polysilicates having variable layers of the chlorite type and tectopolysilicates, such as
zeolites, preferably of type Y in its H-form.
If required, such acidic polysilicates can be activated by treatment with acid and/or by
treatment with a metal salt solution and/or by drying, and in the case of zeolites
preferably by ion exchange and/or by heating.
Particularly suitable is montmorillonite K10 (for example from Sud-Chemie), being a
sheet silicate of the smectite type, which can act both as Bronstedand as Lewis ac\6.
Montmorillonite K10 is inexpensive, non-toxic and not dangerous and is accordingly
suitable in particular for carrying out the process according to the invention on an
industrial scale.
In another preferred embodiment, the acid is attached to a carrier, whereas the carrier
being attached to the acid is a solid at filtration temperature. Suitable carriers are, for
example, polystyrenes, polyethylene glycols, polyacrylamides, silicon dioxide,
controlled pore glass (CPG) or resin beads. Since the combination compound of acid
and carrier is a solid at the filtration temperature, it can be filtered off and removed
from the reaction mixture very easily.
In an also preferred embodiment, the substituent R1 of the a-keto ester is a straightchain
or branched alkyl group with 1-3 carbon atoms. The process according to the
invention can be used in particular for purifying methyl 2-oxobutyrate. The advantages
of the present invention are particularly evident in the case of methyl 2-oxobutyrate
since the corresponding secondary and tertiary alcohol by-products cannot be
esterified, for example, with acetic anhydride alone or in combination with
A^/V-dimethylaminopyridinePMAP).
Preferably, the carboxylic anhydride used is acetic anhydride. Compared to other
carboxylic anhydrides, acetic anhydride is relatively cheap and can be obtained in
large amounts. Moreover, with respect to the so called "Atom Economy", the use of
acetic anhydride is particularly advantageous since the total amount of waste can be
kept at a minimum. Preferably, acetic anhydride is employed in an amount of less than
50 percent by weight, based on the amount of the crude a-keto ester product, for
example in an amount of 2-25 percent by weight, in particular in an amount of 5-
15 percent by weight.
(o
The acid employed in step (a) is preferably used in catalytic amounts. In this manner,
the process costs can further be reduced, and the risk of any unwanted side reactions
during the esterification is kept at a minimum. The acid is preferably employed in an
amount of less than 20 percent by weight, based on the amount of the crude a-keto
ester product, more preferably in an amount of less than 10 percent by weight, for
example in an amount of 2-5 percent by weight.
It is particularly advantageous, if the acid is recycled after filtration, i.e. after step (b). In
this manner, the costs of purifying the a-keto ester can be reduced even further.
Moreover, there are less costs for the disposal of the acid.
The present invention furthermore relates to the use of montmorillonite K10 for
purifying an a-keto ester, in particular methyl 2-oxobutyrate. Here, montmorillonite K10
is used in combination with a carboxylic anhydride, in particular with acetic anhydride,
to esterify any alcoholic by-products present, so that they can be removed afterwards
by distillation.
The present invention is now illustrated in more detail by the examples below. Example
1 relates to a process according to the invention, whereas examples 2 and 3 describe
esterification experiments under different reaction conditions.
Example 1
In a 1 L round-bottom flask, 737.2 g of methyl 2-oxobutyrate to be purified, with a
methyl 2-oxobutyrate content of about 62%, 69.5 g of acetic anhydride and 23.9 g of
montmorillonite K10 are stirred on a rotary evaporator at 50 °C for one hour. The
reaction mixture is then filtered through a glass suction filter. Distillation at a head
temperature of 48-50 °C and a pressure of 15mbar affords 360 g of methyl
2-oxobutyrate having a methyl 2-oxobutyrate content of more than 98%.
The results of the product analysis by gas chromatography are summarized in table 1.
Table 1
Crude product
Filtered product*
Relative content of
methyl 2-oxobutyrate
92.50%
99.97%
Relative content of
secondary alcohol
3.97%
0.03%
Relative content of
tertiary alcohol
3.53%
—
" Before distillation.
7
Example 2 (comparative example)
5.0 g of methyl 2-oxobutyrate to be purified and 0.5 g of acetic anhydride are stirred for
one hour at 40 °C, 60 °C and 80 °C, respectively. The reaction mixture is then filtered
through a glass suction filter.
The reaction mixture is analyzed by gas chromatography. The results are summarized
in Table 2.
Table 2
Crude product
40 °C
60 °C
80 °C
Relative content of
methyl 2-oxobutyrate
91.72%
91.50%
91.61%
91.57%
Relative content of
secondary alcohol
5.58%
5.50%
5.57%
5.52%
Relative content of
tertiary alcohol
2.75%
3.00%
2.82%
2.91%
Example 3 (comparative example)
5.0 g of methyl 2-oxobutyrate to be purified, 0.5 g of acetic anhydride and 25 mg of
DMAP are stirred for one hour at 40 °C, 60 °C and 80 °C, respectively. The reaction
mixture is then filtered through a glass suction filter.
The reaction mixture is analyzed by gas chromatography. The results are summarized
in Table 3.
Table 3
Crude product
40 °C
60 °C
80 °C
Relative content of
methyl 2-oxobutyrate
91.72%
90.21%
91.54%
91.30%
Relative content of
secondary alcohol
5.58%
5.80%
4.74%
4.84%
Relative content of
tertiary alcohol
2.75%
3.99%
3.72%
3.86%
£

We Claim:
1. A process for purifying an a-keto ester of formula
0 (I),
wherein R1 is a saturated alkyl group with 1-5 carbon atoms, and R2 is a
saturated alkyl group with 1-5 carbon atoms or is a benzyl group,
having a content of secondary and tertiary alcohols of formula
R3 OH
wherein R1 and R2 are as defined above and R3 is hydrogen or a saturated alkyl
group with 1-5 carbon atoms,
characterized in that
(a) the a-keto ester of formula I, which is to be purified, is treated with a
carboxylic anhydride and an acid, said acid being an acidic polysilicate,
which is essentially insoluble under the filtration conditions, for esterifying
the secondary and tertiary alcohols of formula III,
(b) the reaction mixture is filtered to remove the acid, and
(c) the purified a-keto ester is distilled for isolation.
2. The process of claim 1, wherein the acid is a solid at filtration temperature.
3. The process of claim 1, wherein the acid is attached to a carrier and the carrier
being attached to the acid is a solid at filtration temperature.
4. The process of claim 1, wherein the acid is montmorillonite K10.
5. The process of any one of claims 1 to 4, wherein R1 is a straight-chain or
branched alkyl group with 1-3 carbon atoms.
9
The process of any one of claims 1 to 5, wherein the a-keto ester is methyl
2-oxobutyrate.
The process of any one of claims 1 to 6, wherein the carboxylic anhydride is
acetic anhydride.
The process of any one of claims 1 to 7, wherein the acid is recycled after
filtration.
The process of any one of claims 1 to 8, wherein the acid is employed in a
catalytic amount.
Use of montmorillonite K10 in combination with a carboxylic anhydride for
purifying methyl 2-oxobutyrate.
Dated this the /3t h day of October,2010
LNISHA SINGH NAIR
tnt for the Applicant [lN/F¥t^40]
LE/X ORBIS
Intellectual Property Practice
709/710, Tolstoy House,
15-17, Tolstoy Marg,
NewDelhi-110 001
10