Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-22
2001-10-02
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06297386
ABSTRACT:
The present invention relates to a process for preparing 1-alkyl-, in particular also 1,3-dialkyl-pyrazole-5-carboxylic esters, from the enolate of 2,4-dicarboxylic esters and N-alkylhydrazinium salts.
It is already known to prepare 1-alkyl-pyrazole-5-carboxylic esters by alkylation of pyrazole-3-carboxylic esters with alkylating agents (for example alkyl halides, dialkyl sulfates or alkyl tosylates).
Thus, EP Published Specification 463 756 and EP Published Specification 526 004 describe the preparation of ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate by reaction of ethyl 3-n-propyl-pyrazole-5-carboxylate with dimethyl sulfate. Apparently, a mixture is formed here comprising the two isomeric N-methyl-pyrazoles, requiring complicated separation by means of chromatographic methods.
The preparation of ethyl 1-methyl- and ethyl 1-ethyl-3-propyl-pyrazole-5-carboxylate from ethyl 3-propyl-pyrazole-5-carboxylate by alkylation with dimethyl sulfate or triethyloxonium tetrafluoroborate is described in DE Published Specification 19 27 429. No statements are made with respect to the possible occurrence of isomers, their separation or the total yield of the desired product, even though, based on the literature which was then known, the formation of isomer mixtures had always to be considered a possibility. Thus, methylation of methyl 3,4-dimethyl-pyrazole-5-carboxylate with methyl iodide and sodium methoxide as auxiliary base leads to a mixture of the isomeric trimethyl pyrazole carboxylic esters which could be separated into the isomers only “after repeated rectification” (J. Prakt. Chem. 126, 198 (1930)). The ethylation of ethyl 3-methylpyrazole-5-carboxylate with ethyl bromide/sodium in absolute alcohol gives a mixture of ethyl 1-ethyl-3-methyl-pyrazole-5-carboxylate and ethyl 1-ethyl-5-methyl-pyrazole-3-carboxylate in a ratio of approximately 1:3, i.e. the frequently desired 1,3-dialkyl isomer is formed in considerably smaller amounts and is obtained pure only after three-fold distillation (Chem. Ber. 59, 603 (1926)).
The other, frequently used method of preparing 1-alkyl-pyrazole-5-carboxylic esters comprises the reaction of 2,4-diketocarboxylic esters with N-alkylhydrazines. Likewise, isomer mixtures are obtained here which generally contain predominantly the frequently undesirable isomer, which then again necessitates a complicated separation process. Thus, the reaction of ethyl 2,4-dioxopentanecarboxylate with methyl hydrazine gives a 1:1 mixture of 1,5-dimethyl-pyrazole-3-carboxylate and the corresponding 2,4-dimethyl isomer (Austr. J. Chem. 36, 135-147 (1983)). Other authors report even more unfavorable ratios of 35:65 (Chem. Ber. 59, 1282 (1926)), which were confirmed in comparative laboratory experiments, for this reaction. The same authors obtained even worse results (isomer ratio 15:85) with analogous etherified enols, for example with O-ethyl acetone oxalate and methylhydrazine. In general, either the free hydrazines with the diketo ester, or the sodium salt of the diketo ester (enolate) and hydrazine salts, from which the hydrazine is liberated with bases such as sodium hydroxide or sodium carbonate, are employed for these reactions.
The reaction mixtures which are obtained in the preparation processes of the prior art cannot be worked up by distillation, because they contain by-products which prevent distillative separation of the two isomers formed.
According to an earlier proposal by the Applicant, 1-alkyl-pyrazole-5-carboxylic esters are prepared by reacting the enolate of a 2,4-diketocarboxylic ester in the presence of a solvent, for example an alcohol, with an N-alkylhydrazinium salt (German Patent Application 19 701 277.9). The N-alkylhydrazinium salt has to be prepared from alkylhydrazine using an acid in the presence of alcohol. To this end, alkylhydrazines have to be handled in pure form which, owing to their toxicity and explosive properties (see Römpp Lexikon Chemie—Version 1.3 (1997)—methyl-hydrazine is a rocket fuel), is only possible with a particularly high expenditure for safety.
There is therefore still a need for a process for the selective preparation of 1-alkyl-pyrazole-5-carboxylic esters which are as free as possible from isomers, which process does not require such a high expenditure for safety.
This invention, accordingly, provides a process for preparing 1-alkyl-pyrazole-5-carboxylic esters of the formula (I)
in which
R
1
and R
4
independently of one another each represent straight-chain or branched C
1
-C
6
-alkyl, C
3
-C
7
-cycloalkyl or optionally substituted C
7
-C
12
-aralkyl and
R
2
and R
3
independently of one another each represent hydrogen, straight-chain or branched C
1
-C
6
-alkyl, C
3
-C
7
-cycloalkyl or optionally substituted C
7
-C
12
-aralkyl,
which comprises reacting the enolate of a 2,4-diketocarboxylic ester of the formula
in which
R
2
, R
3
and R
4
are each as defined in formula (I) and
M represents the equivalent of a metal atom,
in the presence of a solvent and of water with an N-alkylhydrazinium salt of the formula (III)
R
1
—NH
2
—NH
2
⊕ R
5
COO
&thgr;
(III),
in which
R
1
is as defined in formula (I) and
R
5
together with the COO
&thgr;
moiety represents the anion of an organic acid.
C
7
-C
12
-aralkyl, preferably benzyl, and C
6
-C
10
-aryl (mentioned hereinbelow), preferably phenyl (mentioned hereinbelow), may in each case contain, for example, up to two substituents from the group of the halogen atoms and the C
1
-C
4
-alkyl radicals.
Preferred diketocarboxylic ester enolates of the formula (II) are those where the radicals R
2
and R
3
independently of one another each represent hydrogen, straight-chain or branched C
1
-C
4
-alkyl, C
3
-C
6
-cycloalkyl or optionally substituted benzyl, and also those where the radical R
4
represents straight-chain or branched C
1
-C
4
-alkyl.
Particular preference is given to 2,4-diketocarboxylic ester enolates of the formula (II) where R
2
and R
4
each represent C
1
-C
4
-alkyl and R
3
represents H.
In the formula (II), M preferably represents a monovalent metal atom or an equivalent of a divalent metal atom. Examples are lithium, sodium, potassium, calcium and magnesium. Particular preference is given to sodium, lithium and magnesium.
Preferred N-alkylhydrazinium salts of the formula (III) are those where R
1
represents straight-chain or branched C
1
-C
4
-alkyl or optionally substituted benzyl and R
5
represents straight-chain or branched C
1
-C
6
-alkyl, C
3
-C
7
-cycloalkyl, C
7
-C
12
-aralkyl or C
6
-C
10
-aryl, which may optionally be substituted as mentioned above.
R
5
together with the COO
&thgr;
moiety may also represent an anion of a polybasic organic acid. Examples are anions of oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric, malic, tartaric and citric acid, and they may in each case be mono- or polyanions. Such anions may contain one or more COO
&thgr;
moieties and, if appropriate, additionally also COOH radicals. In the case of anions of polybasic organic acids, the alkylhydrazine can be employed in equimolar amounts, based on the acid, or in amounts which correspond to the number of the acid groups.
The diketo ester enolate of the formula (II) can be prepared, for example, from the corresponding pure isolated 2,4-diketo esters by addition of an alkoxide. Suitable alkoxides are, for example, those which correspond to the formula (IV)
M(OR
6
)
n
(IV),
in which
M is as defined for formula (II),
R
6
represents C
1
-C
4
-alkyl and
n corresponds to the valency of M.
The preparation of the diketo ester enolates of the formula (II) can be carried out in a solvent, for example in a C
1
-C
4
-alcohol.
Diketo ester enolates of the formula (II) can also be prepared according to the customary methods by condensation of a methyl alkyl ketone of the formula (V)
in which
R
2
is as defined for formula (I),
with an oxalic ester of the formula
R
4
OOC—COOR
4
(VI)
in which
R
4
is as defined for formula (I). This reaction is likewise carried out in the presence of an alkoxide, for example an alkoxide of the
Matzke Michael
Muller Nikolaus
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Ramsuer Robert W.
LandOfFree
Method of preparing 1-alkyl-pyrazol-5-carboxylic acid esters does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of preparing 1-alkyl-pyrazol-5-carboxylic acid esters, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of preparing 1-alkyl-pyrazol-5-carboxylic acid esters will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2572432