Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1994-10-03
1996-06-04
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
558169, C07F 910
Patent
active
055234500
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 U.S.C. 371 and was based upon PCT International Application No. PCT/GB92/02408 which was filed on Dec. 31, 1992.
This invention relates to a process for preparing substantially dry GPC, i.e. glycerophosphocholine, in enantiomeric form.
GPC is a valuable material, e.g. as an intermediate in the preparation of pharmaceutical-grade phospholipids. For this purpose, it is required in anhydrous form, but it is then extremely hygroscopic. While various methods are known for obtaining dry GPC, there is no published process which is operable on a commercial scale.
Hanahan, Biochem. Prep. 9 (1952) 55, describes the preparation of GPC as its cadmium chloride complex, following the deacylation of lecithin with alkaline hydroxylamine, followed by neutralisation and extraction. Tattrie et al, Biochem. Prep. 6 (1958) 16-19, describe liberation of free GPC from the cadmium chloride complex and subjection to reduced pressure and elevated temperature, to reduce the water content and give highly viscous GPC, at a bath temperature of 45.degree. C.; drying the syrup under reduced pressure over P.sub.2 O.sub.5 ; dissolving the vitreous product in ethanol and crystallising GPC therefrom with cooling; and filtering the crystalline GPC, washing with ethanol and then ether and removing solvent therefrom under reduced pressure. The product is described as follows: "L-.alpha.-Glycerophosphorylcholine is a white crystalline compound melting at 142.5.degree.-143.degree. with sintering at 141.degree. . The crystalline diester is extremely hygroscopic." It is reported that "the checkers were unable to obtain a crystalline product".
Brockerhoff et al, Can. J. Biochem. 43 (1955) 1777, describe obtaining GPC from egg yolk lipids by precipitation with acetone, removal of acidic phospholipids over Al.sub.2 O.sub.3, dissolution in ether and the addition of aqueous methanolic tetrabutylammonium hydroxide. The precipitate of GPC was dissolved in methanol, re-precipitated with ether and held over P.sub.2 O.sub.5 : "The analyses indicated that the GPC contained 1 mole of water."
A practical method for drying GPC has now been found; the process has similarities to that described by Tattrie et al., but does not require the use of the cadmium chloride complex as starting material, employs a somewhat higher temperature in the first stage of water removal, e.g. 45.degree., 50.degree., 55.degree. C. or higher, and utilises anhydrous ethanol or another suitable solvent directly on the highly viscous GPC. Inter alia, it has been found that the use of phosphorus pentoxide is unnecessary.
Without wishing to be bound by theory, one reason for the greater practicability of the novel process may be more efficient first-stage drying, with a consequent greater difference between that temperature and the relatively cool temperature required for crystallisation (it is of course important that the temperature, or any other condition, should not be such that the enantiomeric form of the GPC is lost). The consequence of the novel process is a useful and apparently novel form of GPC, i.e. L-.alpha.-glycerophosphocholine, m.p. 152.degree. C. Further, it appears that, during the process, a novel alcoholate or solvate of GPC is obtained, in crystalline form.
The following Example illustrates the invention.
EXAMPLE
A 50 jacketed glass vessel with a lid and a glycol-cooled condenser is charged with between 5 and 10 kg wet GPC (water content 10-20%). The vessel is sealed and the contents are stirred at 50 rpm for about 30 min, at a jacket temperature of 65.degree.-70.degree. C. A vacuum pump is connected, and the pressure in the vessel reduced to approx. 0.1 torr.
As the system pressure falls, the contents of the vessel begin to boil. Water vapour condenses out and the volume of distillate is monitored. The pump is operated so as to avoid exceeding the capacity of the condenser, whilst maintaining a steady boil-up rate.
The temperature is monitored, maintaining the GPC at above 55.degree. C. to avoid premature crystallisation. Water re
REFERENCES:
Brockerhoff, H. et al. (1965) "Simplified Preparation of L-a-Glyceryl Phosphoryl Choline" Canadian Journal of Biochemistry, 43: 977.
Tattrie, N. et la. (1958) "L-a-Glycerophosphorylcholine" Biochemical Preparations, 6:16-19.
Hanahan, D. et la. (1952) "L-a-Glycerophosphorylcholine" Biochemical Preparations, 9:55-58.
Evans Christopher T.
McCague Raymond
Tyrrell Nicholas D.
Ambrose Michael G.
Genzyme Limited
Gosz William G.
Richter Johann
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