Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-11
2003-07-22
Rao, Deepak (Department: 1754)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06596865
ABSTRACT:
The invention relates to a process for the separation of phosphoric acid, thiamine triphosphate and higher thiamine phosphates from solutions which contain phosphoric acid and thiamine monophosphate, diphosphate, triphosphate and higher phosphates, characterized in that the phosphoric acid solution of thiamine phosphates is passed over a nonionic adsorber resin which contains unsaturated cyclic nitrogen bases, and thiamine monophosphate and diphosphate are eluted using a suitable solvent.
Thiamine diphosphate (cocarboxylase) is a coenzyme in a number of reactions in which carbon-carbon bonds are cleaved, e.g. in the oxidative decarboxylation of pyruvate to acetyl-CoA and of 2-oxoglutarate to succinyl-CoA, in carbohydrate metabolism and in fermentation processes.
Thiamine diphosphate is employed for the treatment of diabetes, in liver diseases, cardiac insufficiency, convulsions, multiple sclerosis, acidoses etc.
Production on an industrial scale makes the most economical and environmentally compatible preparation necessary.
Customarily, thiamine diphosphate is obtained by phosphorylation of thiamine. In this connection, as a rule a product mixture is obtained which, depending on the reaction conditions, is composed of different proportions of thiamine monophosphate, diphosphate and triphosphate, higher thiamine phosphates and phosphoric acid.
In many cases, the separation of the product mixture is carried out by use of ion exchangers which have a varyingly high affinity for the individual components of the mixture.
Thus DE-A-1 085 527, for example describes that mixtures which contain thiamine monophosphate, diphosphate and triphosphate, higher thiamine phosphates and phosphoric acid can be separated by passing the mixture firstly over a weakly basic ion exchanger, whereby phosphoric acid is removed. The mixture is then led, after a hydrolysis, which is not described in greater detail, of the thiamine triphosphate contained in the mixture, over a cation exchanger, thiamine monophosphate remaining adhered, while thiamine diphosphate is eluted.
It is disadvantageous in this process that the thiamine triphosphate and in general also the higher thiamine phosphates as a rule have to be removed, by hydrolysis or similar measures, from the mixture to be separated before the separation of the thiamine monophosphate from the thiamine diphosphate can take place on the cation exchanger. This means a further process step and is uneconomical for an industrial process.
A similar process is described in GB 793 753, which likewise employs ion exchangers for the separation of the phosphorylation products. In this process, thiamine triphosphate is separated by fractional elution. Since the thiamine tri- and tetraphosphates as a rule have a very similar affinity for the ion exchangers to that of thiamine diphosphate, the elution of the diphosphate overlaps clearly with that of the higher phosphates. The separation of higher thiamine phosphates can therefore as a rule only be achieved with yield restrictions of thiamine diphosphate due to correspondingly large-scale fractionation of the eluate.
A process described in EP 0 385 379 B1, with the aid of which thiamine monophosphate can be separated from mixtures which contains thiamine monophosphate, diphosphate and triphosphate, higher thiamine phosphates and phosphoric acid, likewise proposes employing an ion exchanger and eluting thiamine diphosphate and higher thiamine phosphates using water, while thiamine monophosphate remains on the ion exchanger. In order to obtain the valuable product thiamine diphosphate, the need exists, however, as in the processes mentioned beforehand, to free the thiamine diphosphate from the higher thiamine phosphates according to known methods, which as a rule can be achieved only by yield restrictions of thiamine diphosphate.
It has now been found that phosphoric acid, thiamine triphosphate and higher thiamine phosphates can be separated from solutions which contain phosphoric acid and thiamine monophosphate, diphosphate, triphosphate and higher phosphates if the phosphoric acid solution of thiamine phosphates is passed over a nonionic adsorber resin which contains unsaturated cyclic nitrogen bases, and thiamine monophosphate and diphosphate are eluted using a suitable solvent.
Surprisingly, owing to the use of adsorber resins which contain unsaturated cyclic nitrogen bases, phosphoric acid, thiamine triphosphate and higher thiamine phosphates, essentially tetraphosphate, remain on the adsorber resin and/or are cleaved to thiamine diphosphate, while thiamine monophosphate and thiamine diphosphate are eluted. After removal of the solvent, thiamine monophosphate and diphosphate are obtained in high purity in this way with only very low substance losses.
If an adequate separation of thiamine mono- and diphosphate cannot be achieved by fractional elution, the mixtures of thiamine diphosphate and thiamine monophosphate obtained in this way can be separated by known methods, which are described, for example, in DE-A-1 085 527, GB 793 753 or EP 0 385 379 B1.
Preferably, the mixtures of thiamine diphosphate and thiamine monophosphate are separated by allowing their solutions to run over cation exchangers such as Amberlite IRC 50, IR 100, IR 105 or IR 120 or over cation exchangers which contain aminoethylene and/or iminodimethylenephosphonic acid radicals, such as, for example, Lewatit OC 1060 from Bayer, as such ion exchangers retain thiamine monophosphate and allow the thiamine diphosphate to run through, such that essentially thiamine monophosphate-free solutions of thiamine diphosphate are obtained.
The nonionic adsorber resins are synthetic porous bead polymers which are insoluble in water and organic solvents, where the functional groups, depending on the type and structure of the polymer, can have a more or less polar character. These resins are able to adsorb both anions, cations and uncharged compounds.
Those adsorber resins are preferred which in the polymer-bound form contain the parent structures of the following heterocyclic bases as functional groups: pyrrole, indole, pyridine, quinoline, isoquinoline, acridine, pyridazine, pyrimidine, pyrazine, quinoxaline, pteridine, purine, pyrazole, imidazole, thiazole or oxazole. Preferably, those adsorber resins are used for the process according to the invention which essentially consist of, for example, poly(vinylpyrrole), poly(vinylindole), poly(vinylpyridine), poly(vinylquinoline), poly(vinylisoquinoline), poly(vinylacridine), poly(vinylpyridazine), poly(vinylpyridazine), poly(vinylpyrimidine), poly(vinylpyrazine), poly(vinylquinoxaline), poly(vinylpteridine), poly(vinylpurine), poly(vinylpyrazole), poly(vinylimidazole), poly(vinylthiazole) or poly(vinyloxazole) crosslinked by divinylbenzene or methylenebisacrylamide. Mixtures of various adsorber resins are also suitable.
The invention thus relates to a process for the separation of phosphoric acid, thiamine triphosphate and higher thiamine phosphates from solutions which contain phosphoric acid and thiamine monophosphate, diphosphate, triphosphate and higher phosphates, characterized in that the phosphoric acid solution of thiamine phosphates is passed over a nonionic adsorber resin which contains unsaturated cyclic nitrogen bases, and thiamine monophosphate and diphosphate are eluted using a suitable solvent.
The invention preferably relates to a process for the separation of phosphoric acid, thiamine triphosphate and higher thiamine phosphates from solutions which contain phosphoric acid and thiamine monophosphate, diphosphate, triphosphate and higher phosphates, characterized in that the solution of thiamine phosphates is passed over a nonionic adsorber resin whose polymeric structure is made up of base units which contain at least one of the groups of the formula I or II:
in which one or two of the groups A, B, X, Y and/or Z has/have the meaning N, while the remaining groups are CR, and R independently of one another is H, halogen, alkyl or alkoxy having 1 to 7 C atoms, and thiamine monophosphate and diphosphate
Beschmann Klaus
Diekmann Horst
Krummradt Holger
Wartenberg Frank-Hardi
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Rao Deepak
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