Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-09
2001-09-18
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06291681
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and of the corresponding anhydride.
BACKGROUND OF THE INVENTION
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, is known in the art. For example, Seiter, U.S. Pat. No. 5,151,525 (“Seiter '525”) discloses a process in which phosgene is used as the reagent, in an alkaline-aqueous/organic two-phase solvent system, that causes the linkage of the two secondary nitrogen atoms via a carbonyl group resulting in ring formation. The reaction disclosed in Seiter '525 employs anisole as the essentially water-immiscible solvent.
The phosgene reagent of Seiter '525, however, is highly toxic and potentially explosive under the influence of other gases or certain reaction liquids. Thus, its use is extremely dangerous when carelessly handled, or supervised, and special precautions are required in its transport, storage and use, e.g., the use of safety devices is essential in any apparatus that comes into contact with phosgene.
A process for the production of the aforementioned cyclo acid that also starts from meso-2,3-bis(benzylamino)succinic acid in the form of its dialkali metal salt, but using an alkyl, haloalkyl or aryl chloroformate in place of phosgene for the ring formation, is disclosed in Japanese Patent Publication (Kokai) No. 8270/1976 (“JP 8270/1976”). Although the disclosed process avoids the disadvantages of phosgene outlined above, it still has other equally serious disadvantages, which may explain why the use of chloroformates has hitherto not been adopted. Apart from the high costs involved, some other disadvantages of using chloroformate are, for example, the production of diphenyl carbonate and phenol as unavoidable byproducts. The diphenyl carbonate separates as a viscous mass from the aqueous reaction solution and clogs up the reactor components and the pH probe. For this reason, pH values cannot be reported accurately, which is of critical significance for the controlled performance of the reaction. However, the cyclo acid can only be produced in the desired yield by using phenyl chloroformate, which is the preferred reagent according to the examples disclosed in JP 8270/1976.
The first reaction step of the process disclosed in JP 8270/1976 involves the reaction of phenyl chloroformate with meso-2,3-bis(benzylamino)succinic acid dialkali metal salt, along with the cleavage by hydrochloric acid, forming a monourethane intermediate, which then reacts further to form the cyclo acid. The resulting alkali phenolate reacts with phenyl chloroformate to form the byproduct diphenyl carbonate. The remaining hydrochloric acid can be neutralized by the addition of alkali metal hydroxide solution, whereby the pH value should be neither too low nor too high. If the pH is too low, the meso-2,3-bis(benzylamino)succinic acid precipitates out and cannot be reacted. Moreover, the meso-2,3-bis(benzylamino)succinic acid combines with separated diphenyl carbonate to form a viscous mass, leading to further clogging of the reactor components, including the stirrer. If the pH is too high, the phenyl chloroformate hydrolyzes too rapidly, leading to unnecessary consumption.
Furthermore, the precipitation of the cyclo acid by the addition of a strong acid is difficult to accomplish, since this often separates as a viscous mass, as disclosed in JP 8270/1976, and can result in a further clogging of the reactor components, including the stirrer.
SUMMARY OF THE INVENTION
Accordingly, one object 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, in the form of its dialkali metal salt, which avoids both the use of phosgene as the reagent for the ring formation, and the considerable disadvantages of performing the process according to the aforementioned Japanese Patent Publication.
This object is achieved by carrying out the reaction of meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a mixture of a water-miscible ether and water under alkaline conditions, by which means it is possible to keep the diphenyl carbonate, which is formed in the reaction, in solution. Accordingly, the reaction is performed in a monophasic solvent system which is free from solid byproducts, thus avoiding clogging of the reactor components, including the stirrer.
Another object of the present invention is a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride in which, after carrying out the process as set forth above for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt, but before the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid is isolated, this 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid is converted, by heating with acetic anhydride in an aromatic hydrocarbon as the organic solvent, preferably toluene, into the desired 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride, which is then isolated.
Accordingly, one embodiment of the invention is a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt. This process includes (a) reacting meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a monophasic solvent system consisting of an about 2:1 to 1:1 mixture of a water-miscible ether and an aqueous alkali metal hydroxide solution at a temperature not exceeding about 40° C., (b) converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt by acidification into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and (c) isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid.
Another embodiment of the invention is a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride starting from a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt. This process includes (a) reacting meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a monophasic solvent system consisting of an about 2:1 to 1:1 mixture of a water-miscible ether and aqueous alkali metal hydroxide solution at a temperature not exceeding about 40° C., (b) converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt by acidification into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and (c) isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or converting the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid in step b) to into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride by heating with acetic anhydride in an aromatic hydrocarbon as the organic solvent; and isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride.
And, a further embodiment of the invention is a process for the production of biotin. This process includes (a) providing an intermediate in the biotin production pathway by (i) reacting a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a monophasic solvent system consisting of an about 2:1 to 1:1 mixture of a water-miscible ether and aqueous alkali metal hydroxide solution at a temperature not exceeding about 40° C., (ii) converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt by acidification into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and (iii) isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or converting the 2-oxo-1,3-dibenzyl-cis
Fleckenstein Juergen
Kraemer Bernd
Veits Joachim
Cave Bryan
Haracz Stephen M.
Higel Floyd D.
Roche Vitamins Inc.
Shameem Golam M. M.
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