Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-09
2002-09-03
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06444828
ABSTRACT:
BACKGROUND
The present invention relates to a particularly advantageous process for preparing 1-alkyl-, in particular 1,3-dialkyl-pyrazole-5-carboxylic esters, from 2,4-diketocarboxylic esters and alkylhydrazines, where some or all of the 2,4-diketocarboxylic ester may be employed in the form of its enolate and some of the alkylhydrazine may be employed in the form of an alkylhydrazinium salt.
It is known to prepare 1-alkyl-pyrazole-5-carboxylic esters by reacting 2,4-diketocarboxylic esters and alkylhydrazines with each other. This gives isomer mixtures which generally contain predominantly the isomer which is undesired here, which then necessitates a complicated separation process and keeps the yield of the desired isomer low. Thus, reaction of ethyl 2, 4-dioxo-pentanecarboxylate, which is initially charged, with methylhydrazine gives a 1:1 mixture of 1,5-dimethyl-pyrazole-3-carboxylate and the corresponding 2,5-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.
EP-A 029 363 also describes the synthesis of N-alkyl-substituted pyrazolecarboxylic esters having long alkyl radicals from diketo ester enolate which is initially charged and alkylhydrazine. However, the pyrazole which is isolated in moderate yields is again not the desired pyrazole, since the N-alkyl substituent and the carboxyl group are in 1,3-position and not, as desired, in 1,5-position. In these reactions, either the free alkylhydrazines are reacted with diketo ester which is initially charged, or the sodium enolate of the diketo ester and an alkylhydrazinium salt are initially charged and the hydrazine is liberated with basic compounds (such as sodium hydroxide or sodium carbonate) from the hydrazinium salt.
According to EP-A 854 142, 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 alkylhydrazinium salt. The alkylhydrazinium salt has to be prepared from alkylhydrazine using an acid in the presence of an alcohol. Here, the isomer ratios are favorable, but the amount of undesired isomer is not insignificant and the yield is therefore still not optimal.
There is therefore still a need for a process for the selective preparation of 1-alkyl-pyrazole-5-carboxylic esters in which considerably less of the corresponding 1,3-isomer is formed than in the known processes.
DESCRIPTION
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, optionally halogen-substituted 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, optionally halogen-substituted C
1
-C
6
-alkyl, optionally halogen-substituted C
3
-C
7
-cycloalkyl or optionally substituted C
7
-C
12
-aralkyl,
characterized in that a 2,4-diketo ester of the formula
in which
R
2
, R
3
and R
4
are each as defined in formula (I),
and/or an enolate thereof is reacted
with an alkylhydrazine of the formula
R
1
—NH—NH (III),
in which
R
1
is as defined in formula (I),
and/or a corresponding alkylhydrazinium salt,
if appropriate in the presence of a solvent and/or of water, in such a manner that during at least 90% of the reaction free alkylhydrazine of the formula (III) is present.
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 diketo esters 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, or also those where the radical R
4
represents straight-chain or branched C
1
-C
4
-alkyl.
Particular preference is given to 2,4-diketo esters of the formula (II) where R
2
and R
4
each represent C
1
-C
4
-alkyl and R
3
represents H.
Among the alkylhydrazines of the formula (III), preference is given to those where R
1
represents straight-chain or branched C
1
-C
4
-alkyl or optionally substituted benzyl.
Diketo esters of the formula (II) can be prepared by a conventional method by condensation of a dialkyl ketone of the formula
in which
R
2
and R
3
are each as defined for formula (I),
with an oxalic ester of the formula
R
4
OOC—COOR
4
(V),
in which
R
4
is as defined for formula (I).
The reaction is carried out in the presence of basic condensing agents, for example alkoxides, and of a solvent. The diketo ester of the formula (II), which is obtained as the enolate, can be liberated from the resulting crude reaction mixture by acidification and can be obtained in pure form by customary methods, for example by extraction with an organic solvent, concentration and distillation (see Organicum, 16th edition, 1976, p.472).
Suitable solvents for the reaction of the dialkyl ketones of the formula (IV) with oxalic esters of the formula (V) are, for example, alcohols such as methanol, ethanol, n-propanol, i-propanol and n-, i-, s- and t-butanol. The alkoxide can be prepared by dissolving an alkali metal or alkaline earth metal in the alcohol which corresponds to the alkoxide.
The diketo ester of the formula (II) is reacted according to the invention with the alkylhydrazine of the formula (III) in such a manner that during at least 90% of the reaction free alkylhydrazine of the formula (III) is present. Preferably, free alkylhydrazine is present during 95 to 100% of the reaction. “x% of the reaction” is understood here as meaning that x% of the total diketo ester of the formula (II) which has been employed has been converted.
The most simple manner by which this can be achieved is by initially charging the alkylhydrazine of the formula (III) in an equimolar amount or in excess, if appropriate in a solvent or water, and slowly adding the diketo ester of the formula (II), if appropriate in a solvent. By initially charging the alkylhydrazine of the formula (III), it is ensured that even when stoichiometric amounts of alkylhydrazine and diketo esters are employed, free alkylhydrazine of the formula (III) is present during almost 100% of the reaction.
It is also possible to initially charge a small amount of free alkylhydrazine, for example 10 to 20% by weight of the total amount, and to add simultaneously the remainder of the alkylhydrazine and the diketo ester, both if appropriate in a solvent or water. It is advantageous here to add a small amount of alkylhydrazine first.
Preference is given to using the diketo ester of the formula (II) in the form of an enolate of the formula (VI):
in which
R
2
, R
3
and R
4
are each as defined for formula (I) and
M represents an equivalent of an alkali metal or alkaline earth metal.
If alkylhydrazinium salts are employed, these may correspond to the formula (VII)
[R
1
NH
2
—NH
2
]
+
X
−
(VII),
in which
R
1
is as defined for formula (I) and
X
−
represents the anion of an organic or inorganic acid.
Suitable anions X
−
of inorganic acids are, for example, chloride, bromide, fluoride, hydrogen sulfate, dihydrogen phosphate and hydrogen carbonate. Preferred anions X
−
are those of organic acids. In this case, X
−
in particular represents R
5
COO
−
, where R
5
represents a C
1
-C
10
-aliphatic or a C
6
-C
12
-aromatic radical, each of which may optionally be substituted. R
5
preferably represents formate, acetate, propionate, butyrate
Matzke Michael
Müller Nikolaus
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Henderson Richard E. L.
Murray Joseph
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