Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-07-09
2004-11-09
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S580000
Reexamination Certificate
active
06815560
ABSTRACT:
The present invention relates to a new process for the preparation of 2-hydroxy-4-methylthiobutyric acid. It relates more particularly to a process for the hydrolysis of 2-hydroxy-4-methylthiobutyronitrile.
2-Hydroxy-4-methylthiobutyric acid is known to be used as a methionine analogue for feeding breeding animals and mainly, among these animals, poultry. This product is marketed under the trade marks Rhodimet AT 88™ or Alimet™.
It is known to prepare 2-hydroxy-4-methylthiobutyric acid by various processes for hydrolysing 2-hydroxy-4-methylthiobutyronitrile. The hydrolysis is carried out with an inorganic acid such as hydrochloric or sulphuric acid or it can also be carried out by enzymatic hydrolysis.
It is known according to Patent GB No. 915,193 to hydrolyse 2-hydroxy-4-methylthiobutyronitrile to 2-hydroxy-4-methylthiobutyric acid in the presence of an inorganic acid. That patent describes the continuous hydrolysis with a dilute sulphuric acid of 2-hydroxy-4-methylthiobutyronitrile and the organic acid obtained is recovered by extracting with an ether. Because the hydrolysis is carried out continuously in a stirred reactor, the process described in that patent gives an incomplete hydrolysis of the starting nitrile and consequently the presence of undesirable derivatives which cannot be given to animals without any risk.
It is also known from U.S. Pat. No. 4,524,077 to hydrolyse the same starting nitrile which is 2-hydroxy-4-methylthiobutyronitrile with sulphuric acid in two steps followed by an extraction of the hydrolysis medium with a solvent which is immiscible with water. The two-step process consists, in a first step, in using a sulphuric acid having a concentration between 50 and 70% by weight and at a temperature between 25 and 65° C. The introduction of 2-hydroxy-4-methylthiobutyronitrile is carried out for a period of 30 to 60 minutes and the hydrolysis of the nitrile to the corresponding amide is carried out for a period of 30 to 90 minutes. The 2-hydroxy-4-methylthiobutyramide is then converted to 2-hydroxy-4-methylthiobutyric acid by a subsequent hydrolysis step at a temperature situated in the range going from 70 to 120° C. The final hydrolysis step is carried out with an acid having a content of between 30 and 50% by weight. In practice, this content is obtained by addition of water. Under these conditions, 2-hydroxy-4-methylthiobutyramide is converted to 2-hydroxy-4-methylthiobutyric acid in 60 to 180 minutes. To convert the nitrile to an acid, the molar ratio of sulphuric acid relative to the nitrile is between 1 and 1.1.
U.S. Pat. No. 4,912,257 describes a process where the same nitrile, that is to say 2-hydroxy-4-methylthiobutyronitrile, is hydrolysed with sulphuric acid in such a manner that the molar ratio of sulphuric acid to 2-hydroxy-4-methylthiobutyronitrile is between 0.5 and 2 in order to form a reaction mixture containing 20-50% by weight of sulphuric acid. The mixture is maintained at a maximum temperature of 50° C. in a stirred reactor for 30-60 minutes. The second reaction step is carried out in a second reactor heated at a temperature between 60 and 140° C. for about 5 to 6 hours.
The patent application published under the number WO 96/40630 describes the same two-step hydrolysis reaction. The preferred ratio between sulphuric acid and 2-hydroxy-4-methylthiobutyronitrile is always, at the beginning of the initiation of the reaction, between 1.15 and 1.25 and then, when the reaction is in the stationary phase, between 0.9 and 1.2 and more preferably between 0.95 and 1.05. Many examples have been provided in order to vary this ratio. All the examples where the ratio is less than 0.88 show a 2-hydroxy-4-methylthiobutyronitrile conversion rate of less than 95%, which is considerably insufficient for industrial exploitation. In this patent application, the conclusion is that a sulphuric acid to nitrile ratio of between 1.0 and 1.2 should be used.
The disadvantage of using these quantities of sulphuric acid, of between 1.0 and 1.2 mol per mol of 2-hydroxy-4-methylthiobutyronitrile is the fact that at the end of the reaction, quantities of ammonium sulphates proportional to the quantities of sulphuric acid introduced are found. These high quantities of sulphate cause a major problem of industrial discharge which is increasingly difficult to solve. Moreover, the medium, being highly acidic; becomes very corrosive when hot and requires the use of exotic materials. From the reaction point of view, a ratio of 0.5 would appear to be sufficient, but it has proved chemically ineffective under the conditions used up until now. It would therefore appear to be impossible to go down as regards the molar ratio of the sulphuric acid relative to the nitrile below 0.88 which is the extreme limit which appears to be effective in the patent application mentioned above.
It has appeared quite surprisingly that it is possible to carry out the hydrolysis of 2-hydroxy-4-methylthiobutyronitrile to 2-hydroxy-4-methylthiobutyric acid with excellent yields with a molar ratio of sulphuric acid to 2-hydroxy-4-methylthiobutyronitrile of between 0.6 and 0.88. The use of a molar ratio of between 0.7 and 0.85 is preferred.
Preferably, the first step which is a reaction of hydration of 2-hydroxy-4-methylthiobutyronitrile to 2-hydroxy-4-methylthiobutyramide is carried out in a highly concentrated sulphuric acid medium in the presence of a sufficient quantity of water to carry out this reaction. The rate of this reaction is inversely proportional to the quantity of water. Thus, a quantity of water equal to one mol of water per mol of 2-hydroxy-4-methylthiobutyronitrile is necessary and a molar quantity of water of between 1 and 3.0 is preferred. A molar ratio between the water and 2-hydroxy-4-methylthiobutyronitrile of between 1 and 2.5 is still more preferably used.
This low concentration of water very greatly limits, during the first step, the successive hydrolysis of 2-hydroxy-4-methylthiobutyramide to 2-hydroxy-4-methylthiobutyric acid. It is thus preferable, during this first step, not to produce more than 5%, preferably less than 2% by weight of 2-hydroxy-4-methylthiobutyric acid. It is also preferable, during this first step, to obtain a concentration of 2-hydroxy-4-methylthiobutyramide greater than 95% by weight and preferably greater than 98% by weight. The operating conditions used during this first step are chosen within limits which do not lead to the production of 2-hydroxy-4-methylthiobutyric acid; it is thus preferable to work at a temperature of less than 60° C. and in particular of between 0° C. and 50° C. The reaction is preferably carried out in a continuous system of reactors in series with a residence time of between 15 minutes and 2 hours. The reaction pressure is preferably chosen between 0.01 and 3 bar.
The second step of the reaction is a hydrolysis of 2-hydroxy-4-methylthiobutyramide to 2-hydroxy-4-methylthiobutyric acid; it is carried out in the presence of the remaining quantity of sulphuric acid not consumed in the first step and in the presence of an additional quantity of water avoiding the separation of phases in the reaction medium. This step is preferably carried out in the presence of at least 28% by weight of water. As regards the reaction conditions, the work is preferably carried out at a temperature of between 90 and 130° C. Preferably, the procedure is carried out at a pressure of between 0.5 bar and a pressure of 5 bar. A pressure below atmospheric pressure makes it possible to remove traces of foul-smelling light gases for example of the dimethyl sulphide, dimethyl disulphide and methyl mercaptan type. The small excess of acid and the presence of ammonium hydrogen sulphate greatly limits the corrosive power of the medium at this temperature.
According to a better way of carrying out the process according to the invention, a concentrated solution of 2-hydroxy-4-methylthiobutyronitrile is introduced during the first step or an aqueous solution of 2-hydroxy-4-methylthiobutyronitrile is evaporated. When the procedure is carried out as described a
Garrait Michel
Gros Georges
Finnegan Henderson Farabow Garrett & Dunner LLP
Oh Taylor V
Rhone-Poulenc Agro
Trinh Ba K.
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