Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-22
2002-02-05
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06344565
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the production of a cyclo acid, namely of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, which is an important intermediate in the multi-stage process for the manufacture of biotin (vitamin H).
BACKGROUND OF THE INVENTION
The production of the aforementioned cyclo acid starting from meso-2,3-bis(benzylamino)-succinic acid in the form of its dialkali metal salt is known. Thus, for example, Seiter, U.S. Pat. No. 5,151,525 describes such a process in which phosgene is used as the reagent in an alkaline aqueous/organic two-phase solvent system for the linkage of the two secondary nitrogen atoms via a carbonyl group with resulting ring formation. In this case, anisole is employed as the essentially water-immiscible solvent for the reaction.
However, as is known, the reagent phosgene is highly toxic and, moreover, potentially explosive under the influence of other gases or certain reaction liquids, so that its use is extremely dangerous when it is carelessly handled or supervised, and special precautions are required in its transport, storage and use, e.g. the employment of safety devices in the apparatus.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process that overcomes certain of the above-referenced disadvantages for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid in the form of its dialkali metal salt using an alternative reagent for the ring formation. This object is achieved surprisingly well with the alternative reagent carbonic acid bis(trichloromethyl ester), also known as “bis(trichloromethyl) carbonate” or—abbreviated and referred to repeatedly hereinafter—“triphosgene,” and in other respects by carrying out the process under particular reaction conditions.
One embodiment of the present invention is a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt, which process includes reacting meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with triphosgene in a two-phase solvent system consisting of an aqueous alkali hydroxide solution and an organic solvent at a temperature not exceeding about 50° C., and converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt, which is present in the aqueous phase, into the desired 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid by acidification.
Another embodiment of the invention is a process for preparing 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid. This process includes reacting an aqueous solution of meso-2,3-bis(benzylamino)-succinic acid with an alkali metal hydroxide solution to form an alkaline aqueous solution of meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt. Meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt is then reacted at a temperature below about 50° C. with triphosgene in a two-phase solvent system, the two-phase solvent system consisting of an aqueous phase of an aqueous alkali hydroxide solution and an organic phase of an organic solvent. The resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidine-dicarboxylic acid dialkali metal salt in the aqueous phase is then acidified to form 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid.
DETAILED DESCRIPTION OF THE INVENTION
The following Reaction Scheme is a structural representation of the process in accordance with the invention:
In the above Reaction Scheme, the alkali metal ion M
+
is either the sodium ion or the potassium ion, preferably the potassium ion, so that the disodium or dipotassium salt, preferably the latter, is used as the starting material for the process in accordance with the invention.
The triphosgene used in the present process is a white, crystalline product in the pure state with a melting point of 78° C.-80° C. It may be distilled without decomposition at a boiling point of 203° C. to 206° C. under atmospheric pressure (760 mm Hg/0.1013 MPa). Its decomposition temperature is above 350° C. Triphosgene decomposes only slowly in air and may therefore be significantly safer to handle than phosgene in air. As is known, triphosgene may be produced in good yield and quality by the photochlorination of dimethyl carbonate and has also been commercially available in large amounts for many years.
For the production of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt, the acid itself is suspended in water, preferably deionized water, and the resulting suspension is treated with an alkali metal hydroxide solution, i.e. sodium or potassium hydroxide solution, preferably potassium hydroxide solution, generally at a pH value of about 9 to about 14, preferably at a pH value of about 12 to about 13. Such a treatment yields a clear, alkaline aqueous solution of the desired dialkali metal salt. Suitable amounts of water and added alkali metal hydroxide solution are used to ensure that the concentration of the meso-2,3-bis-(benzylamino)-succinic acid dialkali metal salt formed amounts to about 5 to about 20 weight percent, preferably about 10 to about 15 weight percent, based on the total weight of the resulting clear alkaline aqueous solution at a pH of about 9 to about 14. The concentration of the added alkali metal hydroxide solution is not critical, although it amounts to about 45-50 weight percent when commercial alkali metal hydroxide solution, e.g. potassium hydroxide solution, is used.
In the present invention, the two-phase solvent system consisting of aqueous alkali metal hydroxide solution and an organic solvent, in which the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt and the triphosgene are reacted with one another, is formed by combining the above-described clear alkaline aqueous solution of the first reaction participant with a solution of the triphosgene in the organic solvent. An aprotic organic solvent may be used as the organic solvent. Representative, non-limiting examples of aprotic organic solvents that may be used in the present invention include an aliphatic or cyclic ether, e.g. diethyl ether or, respectively, tetrahydrofuran or dioxan; an aliphatic or alicyclic hydrocarbon, e.g. hexane, octane or cyclohexane; an aliphatic or cyclic ester, e.g. ethyl acetate or &ggr;-butyrolactone; or an aromatic hydrocarbon, e.g. benzene or toluene. Tetrahydrofuran or toluene is preferably used as the organic solvent. The concentration of the solution of the triphosgene in the solvent may vary, its upper limit depending, of course, on the employed solvent. The concentration of the triphosgene is, however, not critical, although on ecological and economical grounds it is preferably as high as possible.
In the combination of the alkaline aqueous solution of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with the solution of the triphosgene in the organic solvent (the “reaction participants”), the former solution is heated to an elevated temperature in the range of about 30° C. to about 50° C., preferably in the temperature range of about 40° C. to about 45° C. prior to the combination. If desired, the solution of the triphosgene may also be heated to the corresponding temperature prior to the combination. The heating may also be effected for the first time during the course of the combination or thereafter.
The sequence of combining the reaction participants is not critical, i.e. the solution of the triphosgene may be added to the alkaline aqueous solution of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt or the alkaline aqueous solution may be added to the solution of the triphosgene. The former sequence is preferably effected. In this case, it has been found to be advantageous to add the solution of the triphosgene rather slowly and continuously, e.g. dropwise. In order to achieve a good intermixing during the combination, the mixture is suitably stirred or otherwise intermixed.
With resp
Bryan Cave LLP
McKane Joseph K.
Murray Joseph
Roche Vitamins Inc.
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