Process for the synthesis of diricinoleyphosphatidylcholine

Details Process for the synthesis of diricinoleyphosphatidylcholine Process for the synthesis of diricinoleyphosphatidylcholine

1999-08-04

2001-10-02

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S083000, C554S080000

Reexamination Certificate

active

06297391

ABSTRACT:

The present invention relates to a process for the synthesis of diricinoleylphosphatidylcholine (I) with good yields and a high purity.
The compound having formula (I) has been identified in ricinus seeds as an essential intermediate in the synthesis of triglycerides (M. Frentzen, “Acyl-transferases and Triacylglycerols” in “Lipid metabolism in plants”, T. S. Moore, ed. CRC Press, New York, 1993, VI, pages 195-299).
The compound having formula (I) can be used in the detergent and cosmetic industries as an integrator or emulsifying agent or as a component in pharmaceutical and food formulations. The preparation of phosphatidylcholine by the direct synthesis of glycerophosphatidylcholine with a fatty acid (JP0499783), is known in the art. Operating according to this method, however, when ricinoleic acid is used, compound (I) is not obtained but only its condensation products.
It has now been found that it is possible to obtain diricinoleylphosphatidylcholine (I) with good yields and a high purity by means of a simple and economically convenient synthesis process illustrated in FIG.
1
.
In accordance with this, the present invention relates to a process for the synthesis of diricinoleylphosphatidylcholine having formula (I) which comprises:
a) esterifying the terminal carboxylic group of ricinoleic acid (III) with an alcohol having from 1 to 4 carbon atoms to give the corresponding ester having formula (IV);
b) protecting the hydroxylic group of the ester of ricinoleic acid (IV) with a protecting group removable under bland operating conditions and isolating the ester of ricinoleic acid of which the hydroxylic group (V) is protected;
c) hydrolyzing the ester of ricinoleic acid of which the hydroxylic group (V) is protected and isolating the ricinoleic acid of the hydroxylic group (VI) is protected;
d) acylating L-&agr;-glycerophosphatidylcholine (II) with an imidazolic or triazolic derivative of the compound having formula (VI) and isolating the diricinoleylphosphatidylcholine of which the hydroxylic group (VII) is protected;
e) removing the protecting group from the hydroxylic group of the compound having formula (VII); and finally
f) recovering and purifying the compound having formula (I) by means of chromatography.
Step a)
In step (a) of the process of the present invention ricinoleic acid having formula (III) can be prepared by means of the saponification of castor oil using, for example, the method described by A. H. Blatt in “Organic Synthesis”, Vol. II, page 53, ed. J. Wiley pub., New York, 1959. The product thus obtained, which has a titre of less than 90% and a dark yellow colour, is purified by means of fractionated crystallization or, preferably, by means of extraction with an organic solvent selected from tetrahydrofuran, dioxane, dimethoxyethane or ethers, such as for example diethyl ether, diisopropyl ether or dibutylether.
Diethyl ether and tetrahydrofuran (THF) are preferably used. In particular the latter method allows ricinoleic acid (III) with a purity higher than 99%, to be obtained.
Step b)
In step (b) of the process of the present invention, the rinicoleic acid (III) is esterified by reaction with an alcohol having from 1 to 4 carbon atoms to form the ester of this compound at the carboxylic end group (IV). Methyl alcohol is particularly preferred among the various alcohols.
The reaction is carried out by putting compound (III) and the alcohol in contact in a molar ratio ranging from 1:10 to 1:50, preferably from 1:20 to 1:40, in the presence of gaseous hydrochloric acid, and operating at a temperature ranging from 0 to 50° C.
The reaction is preferably carried out at 0° C. for about 10 minutes and then at room temperature (20-25° C.) for about 30 minutes.
The ester of rininoleic acid is then recovered and purified according to the known methods.
Step c)
In step (c) of the process of the present invention the hydroxylic group of the ester of ricinoleic acid (IV) is protected by means of reaction with a protecting group selected from:
1) 2-methoxy-ethoxymethylchloride (MEMCl) CH
3
OCH
2
CH
2
OCH
2
Cl;
2) 2,2,2-trichloethloethylchloroformiate (TROC) Cl—COO—CH
2
CCl
3
3) chloromethyl-methyl-ether CH
3
—O—CH
2
Cl
4) chloromethylmethylsulfide CH
3
—S—CH
2
Cl
Among these 2-methoxy-ethoxymethylchloride and trichloroethylchloroformiate are particularly preferred for the purposes of the present invention.
These two groups have characteristics of stability under the reaction conditions of the process and can be easily removed under bland hydrolysis conditions.
Step d)
In step (d) of the process of the present invention the ester of ricinoleic acid having formula (V) is hydrolyzed. In particular, when the protecting group is MEMCl, alkaline hydrolysis conditions are adopted.
When, on the other hand, the protecting group is TROC the hydrolysis is carried out in the presence of enzymes such as for example the lipase of Pseudomonas.
At the end of the hydrolysis, the compound having formula (VI) is separated and recovered.
Step e)
In step e) of the process of the present invention L-&agr;-glycerophosphatidylcholine (GPC) (II) is acylated with an imidazolinic or triazolinic derivative of ricinoleic acid of which the hydroxyl group is protected (VI).
Compound (II) can be obtained by the hydrolysis of soya lecithin or it can be synthesized starting from isopropylideneglycerol as described, for example, in the patent EP-486.100.
The acylation reaction is carried out in a solvent selected from N,N′-dimethylformamide, dimethylsulfoxide, tetramethylurea, N-methylpyrolidone in the presence of an anhydrous alkaline carbonate.
N,N′-dimethylformamide (DMF) is preferably used as solvent.
Examples of alkaline carbonates are selected from sodium carbonate, potassium carbonate, cesium carbonate.
A quantity of carbonate which is such as to give a molar ratio ranging from 0.1 to 5 moles per mole of GPC, is generally used. The DMF is used in a quantity ranging from 1000 to 2000 ml per mole of GPC. The imidazolinic or triazolinic derivative of O-protected ricinoleic acid is used in equimolecular quantities or with moderate excesses with respect to the GPC (II).
The temperature at which the acylation reaction is carried out is between 20 and 80° C. It is preferable to operate at room temperature and the corresponding times are those required to end the reaction.
Step f)
In step (f) of the process of the present invention the protecting group is removed from the hydroxyl group. When the protecting group is MEMCl, the reaction can be carried out according to the method described by Monti et al., 1983 (Synth. Commun., 13, page 1021) which uses the pyridine salt of p-toluenesulfonic acid. This method allows the complete removal of the protecting group, obtaining a deprotected product with a good optical purity.
When the protecting group is TROC, the method described by Windholz and Johnson, (Tetr.Lett. page
2555, 1967) which uses Zn and CH
3
—COOH, can be used.
The product (I) thus obtained can be further purified adopting one of the conventional techniques.
The homogeneity of the compound thus obtained is tested by gaschromatography, whereas their identity is determined by spectroscopic techniques (NMR, mass spectrometry).
The following examples which have the sole purpose of describing the present invention in more detail, should in no way be considered as limiting the scope of the invention itself.


REFERENCES:
patent: 0 514 694 A1 (1992-11-01), None
Greene, Protective Groups in Organic Synthesis, p. 10-13, 159, John Wiley and sons, 1985.*
Properties of unusual phospholipids. III: Synthesis, monolayer investigations and DSC studies of hydroxy octadeca(e)noic acids and diacylglycerophosphocholines derived therefrom, Chemistry and Physics of Lipids 90 (1997) 117-134.*
Properties of unusual phospholipids. III: Synthesis, CAPLUS registry file AN 1997:758864 rn 204009-48-3P.*
Paulus et al, Gas-liquid chromatographic determination of castor oil as methyl ricinoleate in lipstick, AN 1972:452220.*
Riebel, Preparation of N-phosphonomethyl glycine esters, Abstract and citation, AN 1997:

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