Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-12-05
2001-10-16
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S315000, C568S345000, C568S347000, C568S390000, C568S391000, C568S392000
Reexamination Certificate
active
06303823
ABSTRACT:
The invention relates to a process for preparing ketones by a so-called “crossed aldol condensation” of a ketone with an aldehyde in the presence of a catalyst system consisting of approximately equimolar amounts of a secondary amine and a carboxylic acid, to form an &agr;,&bgr;-unsaturated ketone and, where appropriate subsequent catalytic hydrogenation.
The process is used in particular for preparing 6-methyl-3-hepten-2-one by reacting acetone with isovaleraldehyde, or for preparing the product of the hydrogenation of 6-methyl-3-hepten-2-one, 6-methylheptan-2-one (MHA), which is important as a precursor for numerous active substances, in particular for preparing lipid-soluble vitamins such as vitamin E.
The use of the aldol reaction for assembling higher ketones or aldehydes is widely used in organic synthesis and is extensively documented in the scientific literature. A review concerning this is provided inter alia by the work Houben-Weyl,
Methoden der organischen Chemie,
Volume 7/1, 4th edition, 1979, pages 77 et seq. and Volume 7/2b pages 1449 et seq.
Besides acid-catalyzed variants, aldol condensation methods with base catalysis are known, employing in many cases the hydroxides of the alkali metals and alkaline earth metals or else basic ion exchangers (cf. literature cited above).
The use of amines as catalyst for the aldol condensation has also been previously described in the literature (cf. Houben-Weyl,
Methoden der organischen Chemie,
Volume 7/1, 4th edition, 1979, pages 87 et seq. and Volume 7/2b, pages 1452 et seq.).
A disadvantage of the aldol condensation is, especially when the aldol condensation is carried out, for example, between a ketone and an aldehyde (i.e. a so-called “crossed aldol condensation”), that the selectivity is unsatisfactory; this is because the reactants in this case frequently undergo self-reaction to a large extent. This problem can in many cases be solved by specific preparation of an enamine of one of the reactants and further reaction thereof, as described, for example, by H. D. Engels et al. in Chem. Ber. 95 (1962), pages 1495-1504, or in the reference Dokl. Akad. Nauk SSSR, 149 (1963), page 94. However, increasing the selectivity in this way is at the expense of the need for another synthesis stage, including the appropriate work-up operations.
Although this process variant can be carried out without separate isolation of the enamine in the presence of an acid, according to the results of K. Eiter in Ann. 658 (1962), pages 91-99, the yields of this are only poor if both reactants are able to form an enamine.
Accordingly, the patents U.S. Pat. No. 5,214,151 and EP 0 771 780 have also described and claimed only aldol condensation of acetone with aromatic aldehydes, i.e. aldehydes unable to form enamines, in the presence of a secondary amine.
A complex catalyst system consisting of a secondary amine, a halogen acid and a carboxylic acid is claimed in the process disclosed in EP 0 429 603 B1 for addition of formaldehyde, in particular paraformaldehyde, onto ketones.
The preparation of 6-methyl-3-hepten-2-one by an aldol condensation of acetone with isovaleraldehyde in the presence of aqueous sodium hydroxide solution in relatively good yield has also been known for a long time (cf. Berichte 33 (1900), pages 559-566, in particular page 561).
One possibility for direct industrial preparation of MHA and similar ketones was offered, for example, by the process disclosed in DE 26 15 308, in which an aliphatic ketone, preferably acetone, can be reacted with an aliphatic aldehyde, for example isovaleraldehyde, in the presence of hydrogen and of a catalyst system which catalyzes both the condensation of ketone and aldehyde and the subsequent hydrogenation, at temperatures of 80-280° C. The process is advantageously carried out continuously over a fixed bed catalyst. When carried out industrially, yields of more than 80% of theory can be isolated. The disadvantage of this process is, at the most, that relatively high temperatures must be used, leading to the risk of unwanted byproducts due to overhydrogenation.
EP 765 853 A1 describes a process for preparing MHA by aldol condensation in which acetone and isovaleraldehyde are condensed in the presence of a basic compound to give 4-hydroxy-6-methylheptan-2-one, and the resulting condensation product is hydrogenated under dehydrating conditions. The particular disadvantage of the process is that the condensation in the first process step proceeds only with inadequate yields. Thus, as proved by the examples, the yields determined by gas chromatography after the condensation for 4-hydroxy-6-methylheptan-2-one and the directly formed 6-methyl-3-hepten-6-one total only 76.1% in Example 1 and 80.6% in Example 2. Since there is also loss of required product through elaborate work-up steps and, as proved by the examples, the maximum yields achieved in the subsequent hydrogenation under dehydrating conditions are only 92%, the maximum yields which can be achieved in this process are, despite the elaborate process management, only 74%, which is inadequate for an industrial process.
EP 816 321 A1 discloses a process for preparing 6-methyl-3-hepten-2-one by crossed aldol condensation in which isovaleraldehyde and aqueous alkali containing a basic substance are introduced at elevated temperature continuously into excess acetone. The disadvantage of this process is that the yield of 6-methyl-3-hepten-2-one determined by gas chromatographic analysis is 66% of theory which is absolutely unsatisfactory.
EP 816 321 A1 further discloses in claim 11 a process for preparing 6-methylheptan-2-one or its homologs in which hydrogen, acetone and an aldehyde are said to be reacted in the presence of aqueous alkali containing a basic substance, and of a conventional hydrogenation catalyst. The disadvantage of this process is that the selectivities determined by gas chromatography for 6-methylheptan-2-one in most of the examples of this process are less than 70% of theory. In the single more advantageous example, the selectivity after work-up is only about 82%.
It is an object of the present invention to develop a process for the industrial preparation of ketones, in particular 6-methyl-3-hepten-2-one, by crossed aldol condensation of acetone with an aliphatic aldehyde, in particular with isovaleraldehyde, and, where appropriate, subsequent hydrogenation to 6-methylheptan-2-one, which permits the ketone to be prepared on the industrial scale even without use of very high temperatures and without elaborate work-up steps during the ketone synthesis and with very good selectivities.
We have found that this object is achieved because it is possible even with ketones and aldehydes which are capable of self-condensation under the conditions of an aldol condensation, and both of which are able to form an enamine, such as acetone and isovaleraldehyde, to carry out a crossed aldol condensation between the aldehyde and the ketone in good yields and with very good selectivities when the reaction is carried out in the presence of a catalyst system which consists of a specific secondary amine such as dimethylamine or pyrrolidine, and of a carboxylic acid containing at least 2 C atoms, in particular acetic acid, adipic acid or phthalic acid. The &bgr;-hydroxy ketone initially produced in aldol condensations is in this case found only in very small amounts in the discharge from the reaction.
The novel process is advantageously carried out in such a way that initially excess ketone is mixed with the secondary amine and the carboxylic acid in the presence of water, and heated, and then the aldehyde, for example isovaleraldehyde, is slowly added. This management of the reaction makes it possible to prepare &agr;,&bgr;-unsaturated ketones with selectivities of more than 92%. The conversion based on the aldehyde, which is employed in less than the stoichiometric amount, is quantitative in this case.
The invention accordingly relates to a process for preparing &agr;,&bgr;-unsaturated ketones of the formula I
in which R
1
is an unbranched or
Kaibel Gerd
Knoll Christian
Kramer Andreas
Melder Johann-Peter
Siegel Wolfgang
BASF - Aktiengesellschaft
Keil & Weinkauf
Richter Johann
Witherspoon Sikarl A.
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