Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-29
1999-10-05
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546298, C07F 958, C07D21366
Patent
active
059626879
DESCRIPTION:
BRIEF SUMMARY
Magnesium pyridoxal-5'-phosphate glutamate is known from DE 24 61 742. In this publication, it is proposed as a medicament for prophylaxis and therapy of metabolic disturbances, especially for influencing the lipid and cholesterol state. DE 40 16 963 relates to the use of magnesium pyridoxal-51'-phosphate glutamate for the reduction of LDL-bound peroxides and for prevention of vascular damage.
Considering the importance of magnesium pyridoxal-5'-phosphate glutamate as a medicament, the need exists for a new, simpler and more economic synthesis for this substance. Therefore, an object of the invention is to provide a synthesis of this type.
The object is solved according to the invention by providing a synthesis for magnesium pyridoxal-5'-phosphate glutamate in which pyridoxal-5'-phosphate is obtained as an intermediate product. The pyridoxal-5'-phosphate accumulates in the form of an aqueous solution from which the pyridoxal-5'-phosphate can be isolated if required. However, the obtained pyridoxal-5'-phosphate solution can also be reacted to the end product in an advantageous manner without isolation of the pyridoxal-5'-phosphate. Therewith, the steps required according to the state of the art for purification and drying of the pyridoxal-5'-phosphate are omitted.
A further point of the invention relates to the fact that, starting from pyridoxine, and especially an acid addition salt of pyridoxine, such as pyridoxine hydrochloride, pyridoxal-5'-phosphate is produced in a high yield according to a new method with p-phenetidyl pyridoxal and p-phenetidyl-pyridoxal-5'-phosphate as intermediate products.
Subject matter of the invention is a method for the synthesis of magnesium pyridoxal-5'-phosphate glutamate which is characterised in that: manganese(IV) oxide to pyridoxal; base p-phenetidyl-pyridoxal; 5'-hydroxymethyl group under formation of p-phenetidyl-pyridoxal-5'-phosphate; alkali metal salt of pyridoxal-5'-phosphate; pyridoxal-5'-phosphate; alcoholate and L-glutamic acid; and
A preferred embodiment of the invention is represented in the following reaction scheme. ##STR1##
Molecular weight of the compounds.
__________________________________________________________________________ manganese(IV) oxide
MnO 86,9 g/mol
para-phenetidine (7)
C.sub.8 H.sub.11 NO
137,0 g/mol
para-phenetidyl-pyridoxal
(4)
C.sub.16 H.sub.18 N.sub.2 O.sub.3
286,0 g/mol
para-phenetidyl-pyridoxal-5'-phosphate
(3)
C.sub.16 H.sub.19 N.sub.2 O.sub.6 P
366,0 g/mol
pyridoxal (5)
C.sub.8 H.sub.9 NO.sub.3
167,0 g/mol
pyridoxal-5'-phosphate
(2)
C.sub.8 H.sub.10 NO.sub.6 P
247,0 g/mol
pyridoxal-5'-phosphate monohydrate
(2')
C.sub.8 H.sub.12 NO.sub.7 P
265,0 g/mol
pyridoxine hydrochloride
(6)
C.sub.8 H.sub.12 ClNO.sub.3
205,5 g/mol
magnesium pyridoxal-5'-phosphate
(1)
C.sub.3 H.sub.11 Mg.sub.2..sub.5 N.sub.2 O.sub.9
432,0 g/mol
glutamate
magnesium pyridoxal-5'-phosphate glutamate
(1')
C.sub.13 H.sub.15 Mg.sub.2..sub.5 N.sub.2 O.sub.11
P 464,0 g/mol
dihydrate
__________________________________________________________________________
It has been shown to be advantageous to carry out the individual synthesis steps discontinuously in suitable temperature and pH controlled units under light and/or air exclusion.
In order to be able to monitor the chemical reaction at any time, it is possible to carry out in-process controls for example. In-process controls of this type can comprise analyses, such as HPLC analyses, which can be reliably carried out in a short amount of time (15 min).
Furthermore, it has been shown to be suitable to release the product of each step for further processing first after carrying out an analysis and a purity test.
The individual steps of the synthesis are illustrated in detail in the following.
According to the invention, pyridoxine, preferably in form of an acid addition salt such as pyridoxine hydrochloride (6), is first oxidised to pyridoxal (5). A suitable oxidation agent is manganese(IV) oxide which is suitably used in activated form. The oxidation is then preferably carried ou
REFERENCES:
patent: 3663557 (1972-05-01), Forget
Iwanami et al., "A New Synthesis of Pyridoxial-5-Phospate," Bull. Chem. Soc. Japan (1968), vol. 41 (1) 161-165.
Chemical Abstracts 96; 52138 (1981).
Chemical Abstracts 86: 16550 (1977).
Chemical Abstracts 101; 007040 (1984).
Chemical Abstracts 67; 802109 (1967).
Maidonis Panagiotis
Schneider Werner
Rotman Alan L.
Steigerwald Arzneimittelwerk GmbH
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