Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1992-08-05
1994-04-26
Cintins, Marianne M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
558150, 558133, 558177, 558209, 558110, C07F 910, C07F 9117
Patent
active
053068408
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of L-.alpha.-glycerylphosphoryl-D-myoinositol and the salts thereof from crude or partially purified phosphatides.
BACKGROUND OF THE INVENTION
The preparation of L-.alpha.-glycerylphosphoryl-D-myoinositol (GPI) and the pharmaceutically acceptable salts thereof has not been described up to now.
Brown (J. Chem. Soc., 3774, 1959) and Brokeroff (J. Am. Chem. Soc., 2591, 1959) obtained L-.alpha.-glycerylphosphoryl-D-myoinositol as the cyclohexylammonium salt by acylating pure phosphatidylinositol (PI), a substance which is not commercially available and is obtained by means of a laborious process which cannot be carried out industrially.
Lapage (J. Am. Chem. Soc., 3713, 1960) obtained L-.alpha.-glycerylphosphoryl-D-myoinositol as the cyclohexylammonium salt by acylating maize crude phosphatides but, even though the purification is carried out on strong basic ion exchange resins with gradient elutions, the resulting cyclohexylammonium salt is not pure and repeated crystallizations must be performed in order to purify it.
The difficulty in obtaining pure L-.alpha.-glycerylphosphoryl-D-myoinositol starting from impure phosphatidylinositol (PI) was confirmed by Hawthorne (Biochem. J., 195, 1959), who isolated L-.alpha.-glycerylphosphoryl-D-myoinositol as the barium salt and obtained interesting results only by means of chromatography on strong basic ion exchange resins, with a gradient of a mixture of ammonium formate and sodium tetraborate and using pure phosphatidylinositol.
SUMMARY OF THE INVENTION
The present invention provides a simple and economical process for the preparation of the free acid L-.alpha.-glycerylphosphoryl-D-myoinositol as well as the salts thereof, of general formula (I) essentially consists of purifying crude L-.alpha.-glycerylphosphoryl-D-myoinositol by means of weak basic resins, using diluted aqueous solutions of an organic acid, such as formic acid, propionic or acetic acid. In this manner at first the impurities less acidic than L-.alpha.-glycerylphosphoryl-D-myoinositol, (L-.alpha.-glycerylphosphorylethanolamine (GPE), N-acyl GPE etc.) are removed by washing the resin with a diluted aqueous solution of the organic acid, without eluting L-.alpha.-glycerylphosphoryl-D-myoinositol, then the pure substance is recovered washing the resin with a more concentrated aqueous solution of the organic acid, without eluting the impurities more acidic than L-.alpha.-glycerylphosphoryl-D-myoinositol (L-.alpha.-glycerylphosphorylserine (GPS), glycerophosphoric acid, etc.), which can be eluted only when using saline aqueous solutions, but not with aqueous solutions of organic acids.
This simple purification cannot be achieved when using strong basic resins, since the complete elimination of L-.alpha.-glycerylphosphoryl-D-myoinositol is very laborious and above all since the substance cannot be recovered washing the resin with an aqueous solution of an organic acid: in fact, in this instance, saline aqueous solutions must be used, which involve the use of difficult chromatographic techniques to separate L-.alpha.-glycerylphosphoryl-D-myoinositol from acidic impurities.
The process according to the invention can be summarized as follows:
An alcoholic suspension (preferably in methanol or ethanol) of the mixtures of the crude or partially purified phospholipids is treated with alkali metal alkoxides (preferably sodium or potassium methoxide, ethoxide or tert-butoxide). After the salt formation is complete, the insoluble residue is filtered off and suspended again in the solvent, the suspension is adjusted to neutral or slightly acid pH (preferably from 4 to 7) with a mineral acid (hydrochloric, sulfuric, phosphoric acids) or with an organic acid (preferably formic, acetic, propionic acid), then it is filtered again. The solid containing crude L-.alpha.-glycerylphosphoryl-D-myoinositol Na or GPI K (depending on the alkoxide used is suspended in water (in a water/solid v/w ratio preferably from 1 to 2) and the suspension is added to an alco
REFERENCES:
Lepage et al., Journal of the American Chem. Soc., vol. 82, pp. 3713-3715, (1969).
Hawthorne et al., Biochemistry Journal, vol. 71, pp. 195-200, (1959).
Cintins Marianne M.
Euticals S.p.A.
Page Margaret J.
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