Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-02-07
2003-12-09
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S026000, C562S581000, C564S129000, C426S002000
Reexamination Certificate
active
06660880
ABSTRACT:
The present invention relates to an industrial process for the preparation of 2-hydroxy-4-methylthiobutyric acid esters.
2-Hydroxy-4-methylthiobutyric acid is known to be used as a methionine analogue for feeding breeding animals. This product is marketed under the trade names Rhodimet AT 88™ and Alimet™.
It is known to prepare the 2-hydroxy-4-methylthiobutyric acid by various processes by hydrolysing the 2-hydroxy-4-methylthiobutyronitrile. The hydrolysis can be carried out with an inorganic acid such as hydrochloric or sulphuric acid. Alternatively this reaction can be carried out by enzymatic hydrolysis.
The ester of 2-Hydroxy-4-methylthiobutyric acid is also used as a means of introducing methionine to animals and indeed may be used as an alternative to the acid. It has been found that the ester form is more stable than the acid and that methionine is released from the ester at a rate faster than from the acid form. Thus, the ester form ha become a more favoured means of introducing methionine into the bloodstream of the animal, in particular to ruminants as disclosed in French Patent Application No. 98 14249.
The ester of 2-Hydroxy-4-methylthiobutyric acid may be prepared by esterification of the hydrochloride salt of the acid and then reacting this salt with the alcohol. Such processes are known from U.S. Pat. Nos. 3,850,987 and 3,761,518. It is also possible to prepare the 2-hydroxy-4-methylthiobutyric acid esters by a process which comprises hydrating 2-hydroxy-4-methylthiobutyronitrile with sulphuric acid and then esterifying the product obtained. Such processes are disclosed in U.S. Pat. Nos. 4,524,077 and 4,912,257 and WO 96/40630.
It is known in the art that the monomeric form of 2-Hydroxy-4-methylthiobutyric acid or derivatives thereof exhibit greater biological efficacy than the dimeric and oligomeric forms. Thus, if the product is to be used as an additive in animal feed, it is preferred to produce a product which contains as little as possible dimers and oligomers.
Therefore, when starting from the acid or the salt thereof, in the production of the ester, it is essential that the acid or salt is essentially in the monomeric form. To reduce the amount of dimers and oligomers in the acid, the acid may be purified by various means such as liquid/liquid extraction. This treated acid may then be used to produce the ester.
We have found that 2-hydroxy-4-methylthiobutyric acid esters containing a small amount of oligomers can be produced by the esterification of 2-hydroxy-4-methylthiobutyric acid without the need to pre-treat the acid before the esterification reaction when the esterification reaction is carried out under specific conditions. Indeed, we have found that the ester may be produced from the acid which contains a high amount of oligomers and yet using the process of the present invention, the resulting ester is low in oligomers. Furthermore, we have found that this process is particularly suitable for use as an industrial process.
Accordingly, the present invention provides a process, for the preparation of an ester of 2-hydroxy-4-methylthiobutyric acid which is substantially in the monomeric form, which process, being capable of industrial application and which comprises reacting 2-hydroxy-4-methylthiobutyric acid with an alcohol in the presence of water and an acid catalyst at a temperature of from 30 to 150° C. wherein the acid is the direct product of the hydrolysis of 2-hydroxy-4-methylthiobutyronitrile.
It will of course be understood by the person skilled in the art that the 2-hydroxy-4-methylthiobutyric acid obtained as a direct product of the hydrolysis of 2-hydroxy-4-methylthiobutyronitrile from an industrial process comprises a mixture of monomers, dimers and higher oligomers.
The process of the present invention provides the advantage over the prior art in that there is no need to purify of the acid prior to esterification. This is, of course, an important advantage in an industrial process, avoiding the use of additional large equipment.
In the process of the present invention 2-hydroxy-4-methylthiobutyric acid obtained directly from the hydrolysis of 2-hydroxy-4-methylthiobutyronitrile is reacted with an alcohol. The acid is, thus, likely to be a direct product of an industrial process and will therefore be a mixture of monomers, dimers and other oligomers. The acid may also comprise impurities such as water, sulphuric acid and ammonium sulphate. In particular, the acid may be produced from an industrial process for the production of 2-hydroxy-4-methylthiobutyric acid and may be, for example, Rhodimet™ AT 88, sold by Rhóne Poulenc. Using the process of the present invention, this untreated acid, may be used directly to produce the ester and it is surprising that the resulting ester is low in oligomer content.
The alcohol, suitable for use in the present process, may be an aliphatic alcohol containing 1 to 10 carbon atoms. The alcohol may be linear or branched. Preferably, the alcohol is branched, especially isopropyl alcohol. The use of isopropyl alcohol is particularly preferred as the 2-hydroxy-4-methylthiobutyric acid isopropyl ester has a high biological efficacy.
The acid and the alcohol is suitably reacted in a molar ratio of from 1 to 20. Where the process is operated as a continuous process, the overall molar ratio of acid to alcohol is preferably 1 to 10. The amount of alcohol in the continuous reaction may be maintained at the desired level by recycle. Where the process is operated as a batch process, the molar ratio of acid to alcohol is preferably from 2 to 10. Any unreacted alcohol may be recycled.
The process of the present invention is carried out in the presence of water. The water may be added to the reaction vessel or the water may be produced in-situ. In particular, it has been found that the conversion of acid oligomers is particularly favoured when water is present at the beginning of the esterification reaction.
The process is carried out in the presence of an acid catalyst. Catalysts suitable for use in the process include acids having a pK
a
of less than 3, for example sulphuric acid, xylene sulphonic acid and trifluoroacetic acid. Alternatively, an acid resin may be used to catalyse the process, especially a sulphonic acid resin, for example Amberlyst 15 as produced by Rohm & Haas. The process may also be catalysed using alumina or an aluminosilicate, for example a zeolite or through the use of an enzyme, for example, esterase.
The catalyst may be present in the reaction process in a concentration of suitably at least 0.01 mole of catalyst per mole of 2-hydroxy-4-methylthiobutyric acid, preferably from 0.02 to 0.2 mole of catalyst per mole of acid.
The process may be carried out under atmospheric or elevated pressure. Where the process is carried out under elevated pressure, the pressure may be any suitable pressure, for example up to 50 bar.
The process is carried at a temperature of from 30 to 150° C. Preferably, the process is carried out at a temperature of from 60 to 120° C., especially from 80 to 100° C.
The process may be carried out continuously, semi-continuously or batchwise. In particular for an industrial process, it is preferred to operate a continuous process.
As the process involves an equilibrium reaction, it is preferred to continuously remove water formed in the reaction in order to shift the reaction towards the ester products. The water formed in the reaction may be removed by any suitable means appropriate to an industrial process, for example by distillation. In some cases, the alcohol may be added to form an azeotrope and separated by azeotropic distillation.
The resulting product stream comprises the ester, water, unreacted alcohol, unreacted acid, a small amount of acid oligomers and catalyst. The ester product may be separated from the remaining components of the product stream by any suitable treatment method.
Where the catalyst used in the process is an acid catalyst, the unreacted catalyst in the product stream may be removed by the addition of a base, namely neutralisation. This neutral
Casse Claude
Garrait Michel
Gros George
Adisseo Ireland Limited
Connolly Bove Lodge and Hutz LLP
Oh Taylor V
Rotman Alan L.
LandOfFree
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