Chemical apparatus and process disinfecting – deodorizing – preser – Physical type apparatus – Crystallizer
Reexamination Certificate
1998-12-15
2001-11-13
Hiteshew, Felisa (Department: 1765)
Chemical apparatus and process disinfecting, deodorizing, preser
Physical type apparatus
Crystallizer
C117S200000, C117S206000, C117S900000, C023S301000, C422S258000, C422S259000
Reexamination Certificate
active
06315966
ABSTRACT:
The present invention relates to a continuously operated, two-part crystallizer which is particularly suitable for the resolution of racemic mixtures, and also a separation process for solids mixtures which are difficult to separate, in particular for racemates, using the crystallizer.
In the synthesis of racemates, the two enantiomers are formed in equal amounts, since they have the same energy content. However, it is often the case that only one of the two stereoisomeric forms is required, for example, the 1-amino acids for the formation of proteins. It is therefore necessary to separate the racemate into its optically active components, the l and d forms. The crystallization method has, among other methods, proven useful for the separation of stereoisomers. It is based on the principle that the desired optically active isomer crystallizes preferentially from a supersaturated solution of the racemate when the solution is seeded with a few crystals of this isomer. Examples of this are the separation of the ammonium salt of acylated tryptophan and acylated phenylalanine. Derivatives of aromatic sulphonic acids can likewise be separated in this way, e.g. dl-lysine as the sulphanilic acid salt and dl-serine as the m-xylenesulphonate.
To carry out the crystallization process, various types of apparatus have been proposed. U.S. Pat. No. 3,450,751 describes the use of a tube reactor in which backmixing is very largely prevented for the resolution of racemic glutamic acid, glutamates and their derivatives. A disadvantage of this process is the necessity of continually having to introduce seed crystals of the desired enantiomer into the supersaturated solution of the racemate.
U.S. Pat. No. 3,266,871 proposes the use of a cylindrical vessel which has a conical bottom and is divided into two zones by a wire mesh as crystallizer for the resolution of glutamic acid and its hydrochloride. The mesh opening of the wire mesh is selected such that the seed crystals cannot get into the other part of the vessel while the supersaturated racemic solution can, of course, pass through the wire mesh. Each part of the vessel is equipped with a propeller stirrer which suspends the seed crystals homogeneously in the respective zone. According to the examples in U.S. Pat. No. 3,266,871, this apparatus gives the following results in the resolution of glutamic acid:
Mean
Temper-
Duration of
Purity of
d-Glutamic
Exam-
residence
ature
the process
the l-acid
acid
ple
time (min)
(° C.)
(h)
(%)
(%)
1
7.5
50
10
92.3
92.5
2
6.0
50
7
96.4
95.6
The optical purity of the seed crystals added was 98%. It is conspicuous that, at a constant resolution temperature of 50° C., the purity of the 1-acid after only 7 hours is only 96.4% and after 10 hours is as low as 92.3%. This indicates that although the wire mesh is impermeable to the seed crystals used, it does not present an effective obstacle to very small crystal nuclei. This fact is essentially confirmed in the journal Chemie-Ing.-Techn. Vol. 42, 1970/No. 9/10, pp. 641-644, according to which the industrial resolution of the salt of dl-glutamic acid is carried out at 55° C. in a comparable arrangement and is interrupted after seven hours: the crystals (whose optical purity is at least 95%) are separated off, new seed crystals are added and the entire procedure is repeated. The arrangement thus does not make a genuine continuous process possible, since the crystallized material is regularly replaced completely by new seed crystals at relatively short time intervals.
The contamination of the desired enantiomer with crystals of its mirror image could be prevented if the two ideally mixed zones are completely separated from one another, i.e. if two separate stirred vessels are used. However, the question then arises, as to how the racemic solution gets from vessel to vessel without carrying crystals with it.
A solution to this problem is described, by way of example, for the resolution &agr;-methyl-3,4-dihydroxy-phenylalanine (&agr;-methyl DOPA) in the journal Chemical Engineering, Nov. 8, 1965, pp. 247-248. According to this publication, two stirred vessels are operated in parallel and equal amounts of the supersaturated racemic solution are fed to each. Each vessel is equipped with a suspension pump which conveys the crystal suspension through a special filter. In this motor-driven filter, the filtrate is separated off and returned to the dissolution vessel for enrichment. The thickened suspension flows back into the respective crystallizer.
The disadvantage of this apparatus is finding a suitable filter for separating the filtrate from the crystals. Since no known filter meets the requirements, the authors of the abovementioned article have built a special filter themselves; however, the abovementioned article gives no further details as to the nature of this filter.
U.S. Pat No. 3,892,539 attempts to solve the indicated separation problem for enantiomers by carrying out the selective crystallization in fluidized beds. These consist of a lower part which has a conical configuration and tapers towards the bottom and an upper part which is cylindrical. At the bottom end of the fluidized bed there is an ultrasonic device which breaks up large crystals which settle out. For the resolution of racemic mixtures, preference is given to connecting two fluidized beds in series. The supersaturated racemic solution enters the bottom of the first fluidized-bed crystallizer which is provided with seed crystals of one enantiomer. The seed crystals grow and, depending on their size and the flow velocity of the solution, assume a particular vertical position in the crystallizer. The smallest crystals form a boundary layer in the lower part of the cylindrical bed. In this region, site glasses are provided at various heights of the column, thus enabling the position of the boundary layer to be observed and, based on this, the removal of crystals to be carried out when appropriate. The solution which has been depleted in the respective enantiomer and enriched with the opposite enantiomer leaves the cylindrical fluidized bed at the top and flows to the second fluidized-bed crystallizer arranged downstream.
In the apparatus described, filtration of the solution leaving the first fluidized bed can be omitted provided that, in particular, sedimentation of the smallest nuclei in the upper part of the fluidized bed (above the boundary layer of the crystals) is 100% effective. The flow velocity of the solution keeps the smallest seed crystals in suspension in the lower region of the cylindrical fluidized bed; there is therefore a risk that the significantly smaller crystal nuclei will be carried out at the same flow velocity. Furthermore, the apparatus described in U.S. Pat. No. 3,892,539 has the considerable disadvantage that it is not really possible to change the throughput during operation of the apparatus, because this is associated with an appreciable change in the position of the microcrystal boundary layer.
This makes steady-state operation of the crystallization apparatus considerably more difficult.
It is an object of the invention to develop a crystallization apparatus which should make genuine continuous operation for weeks and months possible and does not have the abovementioned disadvantages.
The seed crystals of one enantiomer should be added only once at the beginning of the production cycle.
The solids concentration should be kept as high as possible in order to achieve (at very low supersaturation) a high space-time yield.
However, the mixing of the solids suspension should nevertheless be homogeneous, i.e. all volume elements of the suspension should have the same particle size distribution.
The crystals obtainable from the crystallizer should be sufficiently large for them to be separated off readily by mechanical means.
The supersaturated feed solution of the enantiomers should be mixed as quickly as possible with the overall solids suspension so that the supersaturation is quickly reduced.
The solution enriched in one enantiomer should flow from the crystallization appa
Baumgard Hans-Dieter
Haedke Bernhard
Himmelreich Josef
Judat Helmut
Haarmann & Reimer GmbH
Hiteshew Felisa
Norris & McLaughlin & Marcus
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