Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1991-11-08
1993-10-05
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C07F 910
Patent
active
052507190
DESCRIPTION:
BRIEF SUMMARY
The present invention refers to a method for the preparation of L-.alpha.-glycerylphosphorylcholine (GPC) and of L-.alpha.-glycerylphosphorylethanolamine (GPE) with very high yields and purity, using as starting materials lecithins of different origin.
The known methods for the preparation of GPC are not suited to the industrial application or yield GPC at very high cost because of the difficulties involved in the purification by crystallisation.
The crystallisation of GPC is infact reliable and gives good yields only when the product itself is already very pure, otherwise, as also reported in Biochem. Preparations 6, 16, 1958, either GPC cannot be purified or the crystallisation yields are very low. In the above cited reference, for instance, the authors use crude egg lecithin but purify GPC by crystallising the complex with cadmium chloride.
The removal of the very toxic CdCl.sub.2 asks for a treatment on high amounts of ion-exchange resins, causing a marked decrease of yeld of pure GPC and preventing the large scale application.
C. Cubrero et al in Chem. Phys Lipids 6, 31, 1971, obtain pure GPC by silica gel chromatography.
This process is very expensive and difficult to apply industrially and gives GPC impure with silicic acid.
DE-A-1,543,722 discloses a method for the recovery of pure, naturally occurring phospholipids from crude lecithins by passing a solution of the crude starting material over a silica gel column and eluting with a mixture of toluene and methanol.
GB 2058792 discloses a process for the preparation of GPC in high purity and suited for large scale operations.
This process circumvents the difficulties of the GPC purification using as starting material very pure phosphatidylcholine. No purification of the obtained GPC is carried out (except the removal of fatty acid esters released in the deacylation of phosphatidylcholine), but the use of very pure and expensive phosphatidylcholine limits the utility of the process which cannot be used, of course, with crude soy or egg lecithins or even with phosphatidylcholine not completely free from other phosphatides or other neutral or acidic hydrosoluble impurities.
EP-A-217765 discloses a process for the preparation of GPC and GPE from crude or deoleated soy lecithins or from crude egg lecithin, through a pure complex of formula (nGPC+mGPE) ZnCl.sub.2 wherein n and m have values from 0 to 1 and m+n=1. The zinc chloride is then eliminated by means of the water insoluble complex ZnCl.sub.2 Py.sub.2 (Py=pyridine) obtaining a water solution of nGPC+mGPE which is then separated on ion-exchange resins. In order to obtain very pure GPC it is however necessary to carry out the deacylation on the ethanol extract of crude or deoleated soy lecithin, obtaining GPC with a yield of about 62% (calculated on the phosphatidylcholine content present in the deoleated soy lecithin).
An higher yield (about 95%) is obtained if the deacylation is carried out on the methanol extract or directly on the methanol suspension of crude or deoleated lecithin but the obtained product has a purity degree not suited for the pharmaceutical use and must be purified again by cumbersome procedure.
The process of the present invention allows the direct preparation of very pure GPC and GPE also from methanol extracts or suspension in high yields and conveniently.
The purification relies on the amphoteric character of GPC and GPE and comprises the elution on a cationic resin in acid form equilibrated in anhydrous solvent of the crude solutions from the deacylation step, washing the resin first with solvent and then with water.
During the elution of the crude deacylated solution in non aqueous medium, GPC, GPE and other basic substances are fixed on the resin, which may then be thoroughly washed with solvent, allowing the complete elimination of all the neutral and acidic impurities, without eluting GPC and GPE.
When the resin is washed with water, since GPC and GPE are very weak bases, the equilibrium between free and resin-bound bases is almost completely shifted towards the free bas
REFERENCES:
Kaitaranta J. Chrom. 206, 327 (1981).
Gerstl Robert
Prime European Therapeuticals S.p.A.
Schneider Walter H.
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