Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1996-02-09
1997-12-09
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
568750, C07C 3768
Patent
active
056963009
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/02520 filed Jun. 28, 1995.
Propofol, or 2,6-diisopropylphenol, having the formula ##STR1## is a well known compound which is largely produced for its use as an antioxydant. Processes for its preparation are described, for instance, in U.S. Pat. No. 2,831,898, U.S. Pat. No. 4,103,096, U.S. Pat. No. 4,208,537, U.S. Pat. No. 4,275,248, U.S. Pat. No. 4,447,657, U.S. Pat. No. 4,538,009, U.S. Pat. No. 4,559,465, JP 62-209034 and SU 443,019. Its use as an anaesthetic for parenteral administration is described in U.S. Pat. No. 4,056,635 and such an use is become common in surgery.
Since propofol is administered by parenteral route, its purity degree must be very high and thus involves fractionated distillations which, on one side, need supplemental apparatus and, on the other side, involves a loss of active principle.
European patent application No. 551,947 discloses a method for the purification of propofol by fractionated crystallisation at very low temperature which, according to the disclosure of the cited document, allows the obtention of 60 g of propofol with a purity of at least 99.90% starting from 100 g of propofol having a purity degree of 99.7%.
It has now been found that a propofol with a pharmaceutical purity for parenteral administration may be obtained by conversion in one of its alkaline metal salt and by neutralization of pure salt thus isolated.
Thus, it is an object of the present invention to provide a process for the purification of propofol which comprises treating the raw product with a base of formula preferably a lower alkyl group of from 1 to 4 carbon atoms, R' is an alkaline or an alkaline-earth metal and n is one or two, depending upon the valence of the metal R', isolating the salt thus obtained and converting it into pure propofol by neutralization with an organic or inorganic acid, preferably with a mineral acid.
According to the process of the present invention, the salification of the phenolic hydroxy group is carried out by treatment with an alkaline agent such as sodium or potassium (C.sub.1 -C.sub.4)alkanoate, for example sodium or potassium methylate or ethylate, sodium amide or such as sodium or potassium hydroxide. Preferably, sodium methylate is used.
The salt forming reaction is carried out in a polar solvent, preferably in an alcohol expecially when an alkaline metal alcoholate is used as an alkaline agent; furthermore, in this case, it is also preferable that the alcohol is the same as the employed alcoholate.
The reaction temperature is of 25.degree.-50.degree. C., preferably of 35.degree.-45.degree. C., and the alkaline metal salt thus obtained is isolated by evaporating the solvent, taking up the residue with an organic solvent wherein the salt of 2,6-diisopropylphenol (propofol) thus obtained is insoluble, and thoroughly washing this salt with the same solvent.
This solid product (the alkaline or alkaline-earth metal salt of 2,6-diisopropylphenol) thus obtained in a pure state is neutralized with an organic or inorganic acid and propofol is isolated by extraction, preferably with toluene, evaporation of the solvent and distillation at about 1.7.times.10.sup.3 pascal.
The neutralization may be made with a mineral acid, such as hydrogen chloride in aqueous solution, or with an organic acid, such as methanesulfonic, formic or acetic acid.
According to a preferred feature, the raw propofol is treated with sodium methylate in methanol at a temperature of 35.degree.-45.degree. C. and, after distilling the solvent at about 2.6.times.10.sup.3 pascal, the oily residue is taken up with toluene. In this solvent, the sodium 2,6-diisopropylphenate separates in a solid state whilst all the impurities remain dissolved. Thus, by filtration and washing with toluene, the still wet, pure sodium salt is isolated and neutralized with an aqueous solution of hydrogen chloride and pure propofol is isolated by extraction with toluene and distillation at 98.degree.-100.degree. C. and 1.7.times.10.sup.3 pascal.
The chemical method, which takes advantage of
REFERENCES:
patent: 3517072 (1970-06-01), Moroni et al.
patent: 3630855 (1971-12-01), Turbun et al.
patent: 3772394 (1973-11-01), Milnes
patent: 5175376 (1992-12-01), Nieminen et al.
Purification of Laboratory Chemicals, Perrin et al, p. 560, Paragraph Labeled "Phenols" 1980.
J. Chem. Soc., Perkin Transactions 1, No. 12, 3229-3231 (1988).
Bellani Piero
Velati Maurizio
Archimica SpA
Barts Samuel
Meller Michael N.
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