CH615191A5 - Process for the preparation of synthetic phospholipids, and their use - Google Patents

Description

The invention relates to a process for the production of synthetic phospholipids, in particular those which do not occur in nature and which are distinguished by a varied phosphorus-nitrogen distance, and the use of these products.

Naturally occurring phospholipids are fat-like triglycerides, which contain two long-chain fatty acids and a phosphoric acid residue to which a base is also attached. They are found in all animal and plant cells, especially in the brain, heart, liver, egg yolk and soybean. The most important naturally occurring phospholipids are the kephalins and lecithins, in which colamine and choline occur as bases.

Lecithins and cephalins are widely used because they have colloidal, surface-active, emulsifying, softening, antioxidant, cleaning and physiological properties. As natural products, they are nutritionally harmless and therefore superior to many synthetic substances with a similar effect. They are added to margarine to achieve better water retention, in chocolate and coating masses the use of lecithin results in faster and better wetting of the mixture components, a reduction in viscosity and thus a considerable saving on expensive cocoa butter. At the same time, rancidity and "fat ripeness" during storage are prevented.

In confectionery, lecithin is used to emulsify syrup with fat. It prevents the fat from becoming rancid and the sugar from crystallizing. Baked goods are easier to process due to the improved wetting when mixing. You can save up to 20% of the otherwise required fat and increase the yield by up to 2% through better water retention.

Large amounts of soy lecithin are also added to animal feed, as this promotes the absorption of food in the intestinal tract and, together with fish and meat meal, counteracts the harmful effects of cholesterol.

In cosmetics and soap production, small additives improve the suppleness and absorption of ointments, creams, toothpaste, soaps, etc.

In the leather and textile industry, lecithin emulsions are used as auxiliary agents during processing because of their antioxidant effect. In paints, the lecithin prevents the pigments from settling and the viscosity is reduced, which results in better processing. It is also possible to improve printing inks for paper and fabrics with lecithin. Pest control uses lecithin emulsions because they have good stability and adhesive strength.

The lecithins and cephalins have recently gained particular importance because they have been found to perform important functions in cell oxidation and other cell processes. However, the function of the phospholipids in cell metabolism is still poorly understood and is therefore particularly difficult since the isolated compounds are obtained only in small amounts and their synthesis is associated with great difficulties. The synthesis of phospholipids often proceeds in many stages and the desired products are only obtained

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with low yields (see A. J. Slotboom and P. P. M. Bonsen, Chem. Phys. Liquids (1970) p. 301).

Lecithin and cephalin are made from natural products, e.g. B. from egg yolk, brain matter, spinal cord and soybeans. The commercial products have very different properties and the use of lecithin and kephalin in different applications is often difficult due to the different content of phospholipids.

The present invention has for its object to provide a synthesis process for phospholipids that is simple and easy to carry out without the need to use expensive starting materials and thereby to obtain new compounds that are similar to the naturally occurring phospholipids and by a combination of lipophilic and hydrophilic, and of acidic and basic groups in the same molecule have similar or better properties than the naturally occurring phospholipids.

This problem is solved with the aid of the method according to the invention, which is characterized in that

A) a polyhydroxy compound in which one hydroxyl group is in free form and the rest are protected, with a to-haloalkylphosphoric dichloride of the formula I.

Cl O

P-P-Alk-X (I),

C1

where X is fluorine, chlorine, bromine or iodine and alk is an alkyl or cycloalkyl radical having at least 3 carbon atoms; and

B) the reaction product obtained with an amine of the formula II

Ri

R3

wherein R 1, R 2 and R 3 independently of one another denote hydrogen or methyl groups.

The synthetic phospholipids produced according to the invention can be used wherever the natural phospholipids are also used. Their use as emulsifiers should be emphasized.

The compounds obtainable according to the invention have valuable pharmacological properties. The lecithinanalo-gene compounds, as highly surface-active substances, have a major influence on natural cell membranes and on the permeability conditions in biomembranes. The properties of the cell membranes can be changed in a targeted manner by varying the phosphate-trimethylammonium distance of the fatty acid and base used.

If the interfacial activity of cell membranes is influenced with the aid of the compounds obtainable according to the invention, the effectiveness of pharmaceuticals changes. H. the resorbability and distribution in the organism are changed.

Due to the pronounced interfacial activity, the compounds obtainable according to the invention cause a change in the properties of cell membranes when administered orally or intraperitoneally to warm-blooded animals. At higher concentrations, cytolytic phenomena are observed. At sublytic doses, changes in cell membranes are caused. Compounds with saturated fatty acid esters of 16 and more carbon atoms, for example palmitic acid, are immunological adjuvants, while with chain lengths of less than 14 carbon atoms an inhibition (immune suppressant action) of the immuno-apparatus could be observed. These results were observed with phosphoric acid choline esters. The immunological adjuvant effect manifests itself in a general increase in the antibody level.

The extensive structural variations that were carried out on the lysophospholipid molecule led to more effective adjuvants.

Phospholipid-dependent enzymes in cell membranes contain natural phospholipid mixtures with a large number of unsaturated fatty acids. Stabilizing such enzyme preparations is difficult because of the instability of the unsaturated fatty acids in the presence of oxygen.

However, such enzyme preparations can be delipidized, losing their enzymatic activity. The reactivation of the enzymes can be achieved with the phospholipids obtainable according to the invention, which contain no unsaturated fatty acid residues. Reactivation is possible if the enzyme is mixed in a suitable ratio with the compound obtainable according to the invention. It is thus possible to reactivate and stabilize phospholipid-dependent enzymes.

According to various authors, hybrid formation and cell fusions are induced by lysolecithin. Cell hybrids can be generated in a similar way to Sendai Virus. The disadvantage is the great cytolytic activity of the lysole cithins from egg lecithin used in these studies. Cell fusion experiments can be optimized by means of the compounds with finely graded cytolytic activity obtainable according to the invention. H. cytolysis can be avoided.

As already indicated above, the compounds obtainable according to the invention are good emulsifiers due to the combination of lipophilic and hydrophilic and of acidic and basic groups in the same molecule and form stable emulsions between pH 0 and 11. They can therefore be used with advantage in detergents. They also have the further advantage that, because of their close relationship with natural phosphatides, they can be broken down in a biological manner and so that pollution problems are avoided. Compounds obtainable according to the invention with more than 6 carbon atoms between P and N also proved to be no longer attackable by phospholiphase C and D, so that their bactericidal and bacteriostatic activity cannot be destroyed by these cell-specific enzymes.

In the process according to the invention, polyhydroxy compounds having a free hydroxyl group are reacted with a haloalkylphosphoric dichloride. The hydroxyl groups in the polyhydroxy compounds can be protected by ether formation, ester formation, ketal formation, etc. In the process according to the invention, poly-, 1,2- or 1,3-diglycerides and other glycerin derivatives, generally polyhydric aliphatic alcohols such as erythritol, pentite and hexite can be used. Examples of polyhydroxy compounds which can be reacted by the process according to the invention are explained in more detail later in connection with the compounds obtainable according to the invention.

Co-bromoalkyl-phosphoric acid dichlorides with preferably 3 to 25 carbon atoms, in particular 3 to 16 and most preferably 3, are preferably used for the reaction

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up to 12 carbon atoms for alkyl groups or 6 carbon atoms for cycloalkyl groups z. B. Cyclohexyl. The halo-alkylphosphoric dichlorides of the desired chain length are obtained by reacting haloalcohols of the following formula:

HO-Alk -X

appropriate chain length, d. H. Alk has the meaning given above, with phosphorus oxychloride. The halogen alcohols mentioned can be obtained from the corresponding diols. For example, the bromo alcohols were prepared by introducing one bromine atom per molecule of diol using a simplified process. The simply-brominated reaction product is removed from the reaction medium by extraction and further bromination is thus excluded.

The reaction of the haloalkylphosphoric dichloride with the polyhydroxy compound is preferably carried out in an inert organic solvent. Inert organic solvents which can be used are, for example, halogenated hydrocarbons, such as chloroform, carbon tetrachloride, benzene,

Toluene, petroleum ether, etc. can be used. The implementation should preferably be carried out with exclusion of moisture. Temperatures in the range from -10 to 50 ° C., preferably in the range from 0 to 20 ° C., are generally used in the reaction. The reaction is preferably carried out in the presence of an inert base, such as, for example, triethylamine or pyridine. In general, the haloalkyl-phosphoric acid dichloride is dissolved in the inert solvent and the base is added. While stirring, the polyhydroxy compound, also dissolved in an inert solvent, is added dropwise to the phosphorylating agent, possibly with cooling.

The implementation is smooth and clear. In general, the implementation is finished after a short time. However, it is advisable to keep stirring for a while to ensure full implementation. Response times in the range of half an hour to 5 hours are common.

The course of the reaction can be followed, for example, by thin-layer chromatography. After the reaction has ended, the solvent and the excess base are removed at low temperature and the reaction product can be separated off by customary processes, for example by extraction. It is generally not necessary to purify the reaction product, but it can be reacted with the desired amine base immediately without further purification.

For this purpose, the reaction product is dissolved in a suitable solvent and an ethanolic or aqueous solution of the corresponding amino base is added. The reaction is carried out at room temperature or slightly elevated temperatures, for example at 55 ° C., 5 to 20 hours or 1 to 6 hours. The course of the reaction can be followed by thin layer chromatography.

It should be noted that the required reaction time is not exceeded ss, since the reaction product decomposes after the reaction has ended.

After it has been determined that the reaction has ended, the reaction product is isolated in a manner known per se. For example, you can clean by column chromatography.

The yields of the analytically pure products are generally between 10 and 25% of theory, based on the diglycerides used or the other corresponding starting materials.

Examples of compounds which can be prepared by the process according to the invention are listed below.

1. Lecithins and cephalins of the following formulas: O

40

HzC-O-

C - Ri O

HC-O-C-R2 O

II ® /

mc-O-P-O-Alk-N ^ -X2

(IV)

O®

O

II

H2C-0-C-R1

O

X3

HC — O —P — O —Alk —N X2

i6

O

(V).

50

H2C-O-C-R2

Starting materials are generally racemic or optically active 1,2- or 1,3-diglycerides with unsaturated, saturated or branched fatty acids or with fatty acids which contain a cycloalkane or aromatic ring.

In the above formulas, Xi, X2 and X3 each independently represent a hydrogen atom or a methyl group, and Alk has the meaning given above.

R 1 and R 2 mean straight-chain or branched saturated or unsaturated alkyl groups, which may optionally also be substituted by a cycloalkyl ring or an aromatic group. The alkyl groups contain 9 to 25 carbon atoms, preferably 12 to 18 carbon atoms and most preferably 14 to 18 carbon atoms. The cycloalkyl groups can contain 5 to 7, preferably 5 to 6, carbon atoms. Phenyl groups or substituted phenyl groups can occur, for example, as aromatic groups. R 1 and R 2 are preferred fatty acid residues, such as residues of palmitic acid, stearic acid.

2. Lyso compounds of compounds of formula IV or

V

The starting materials used to prepare the lyso compounds of the formula IV or V are generally, for example, l-acyl-2-benzylglycerol or l-benzyl-2-acylglycerol. The starting materials can also be produced biochemically from lecithins and cephalins by enzymatic cleavage with phospholipase Ai and A2.

3. Analogues with sugar alcohols

O

II

H2C-O-C-R

O

II

H-C-O-C-R O

60

H-C-O-C-R (VI),

O

II

H-C-O-C-R O

II

H-C-O-C-R O

II V

H2C — O — P —O — Alk — N— 2

i.

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wherein in formula VI Alk, Xi, X2 and X3 have the meanings given above and R has the same meaning as that previously given for Ri and R2. The starting materials used are generally acylated sugar alcohols which contain z-1 acyl radicals in the case of z hydroxyl groups, z is an integer from 2 to 7, preferably 3 to 6, most preferably 4, 5 or 6. It is also possible to use cyclic sugar Use mineral alcohols.

4. ether analogs and ether ester analogs of the compounds of groups 1 to 3 z. B.

H2C-O-R1

H2C-O.

H-C-O

(XI)

10th

H2C-0-P - O - Alk - N -— X:

Ó® ^

X.3

H-C-0-R2

O

(VII)

H2C-0

HC-O.

Xi

H2C-O-P-O-Alk-N X2

(XII).

O-

H2C-O-R1

O

H-C-0-C-R2

O

X3

Xi

H2C-O-P-O-Alk-N-X2 I ^ X3

Oe-

(VIII),

H2C-0 Oe

In the above formulas XI and XII, Alk, Xi, X2 and X3 have the meanings given above, y is an integer from 5 to 32, preferably 5 to 18, more preferably 5 to 16, most preferably 5 to 12. y can thus 5, 6, 7, 8, 9, 10, 11, 12 and so on. In the above formulas, Alk can also contain 2 carbon atoms.

The starting substances are 1,2- and 1,3-cycloalkylketone glycerols, which can be obtained from glycerol or 2-benzylglycerol by conversion with the cycloalkanone in question.

7. Deoxylysolecithins and cephalins

O

wherein in the above formulas VII and Vili Ri, R2, Alk, Xi, X2 and X3 have the meanings given above.

The starting materials are the 1,2- and 1,3-dialkylglycerol ethers and acylglyceryl alkyl ether. 5. Dialkyl ketone glycerol phosphatides

H2C-Q

H2C-O-C-R (CH2) m o

II

H2C-0-P-0-Alk-N X2

(XIII)

H-C-O "^ R2

O

Xi

H2C-O-P-O-Alk-N-X2

ie \ 3

H2C-O

(IX)

H-C-O

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o ©

X3

HsC

(CH2V

O

H-C-O-C-R O

(XIV)

Xi

(X).

O

Xi

H2C-0 —P — O —Alk- N X2

0 ° X,

H2C- O- P - O - Alk-N -— X2

H3C

O®

X3

In the above formulas IX and X, Ri, R2, Alk, Xi, X2 and X3 have the meanings given above.

Starting substances are u. a. 1,2- and 1,3-dialkylketone glycerols or corresponding acetals, which can be obtained from glycerol or 2-benzylglycerol by conversion with the corresponding ketone or aldehyde. The ketone or aldehyde may also contain cycloalkane or aromatic rings in the side chain.

6. Cycloalkyl ketone glycerol phosphatides

(CH2) p

?

H-C-O-C-R p + q = m

(XV).

(CH2) q

O

Xi

H2C-0-P-0-Alk-N-X2

i-

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In the above formulas, Alk, Xi, X2, X3, R have the meanings given above, m is an integer from zero to 14, preferably 1 to 8, most preferably 2, 3, 4, 5 or 6.

The sum of p and q gives m.

Starting substances for compounds of the formulas XIII, XIV and XV are the corresponding monoacylalkanediols, but preferably the co-co'-monoacylalkanediols. The alkanediols can be saturated, unsaturated or branched and can also contain a cycloalkane or aromatic ring.

8.Ather analogs of group 7 compounds

The above classes of compounds are examples of the method according to the invention. The method according to the invention is generally applicable and can be used for the synthesis of many compounds.

The compounds obtained in the process according to the invention can generally be obtained by column chromatography on silica gel. The analytically pure products are white amorphous powders with an uncharacteristic melting behavior. Characterization is therefore generally carried out by thin layer chromatography and elemental analysis.

The following examples illustrate the invention without restricting it.

example 1

Preparation of bromoalcohols of different chain lengths using a simplified process:

Compounds of the following types are synthesized: Br - (CH2) n - OH with Alk = 4 to 10 carbon atoms.

The starting products are diols of appropriate chain length with terminal alcohol functions. Since only one bromine atom is to be introduced per diol molecule, a process must be used in which the reaction product is immediately removed from the actual reaction medium and thus a further reaction is excluded. Extraction is an option for this.

Diol and hydrobromic acid are placed in a round bottom flask. The starting products are overlaid with petroleum spirit or benzene / petroleum spirit. Decisive for the selection of the extractant is the insolubility of the diol and the good solubility of the reaction product therein. The round bottom flask is equipped with a reflux condenser. While stirring vigorously with a magnetic stirrer, the mixture is then heated under reflux until the starting product is completely converted with a patio heater. The progress of the reaction is determined using thin-layer chromatograms.

The extractant phase is then separated off and dried with calcium sulfate. After the desiccant has been filtered off, the extractant is removed on a rotary evaporator. The residue is fractionally distilled in an oil pump vacuum.

The yields are approximately 80 to 95% of theory, based on the diol used.

4-bromo-butanol- (l) and 5-bromo-pentanol- (l) are shown as follows:

22.5 g (0.25 mol) 1,4-butanediol or 26 g 1,5-pentanediol (0.025 mol) are combined with 80 g 47% hydrobromic acid (0.48 mol), 500 ml benzene and 50 ml petroleum spirit ( 100 to 140UC) heated at reflux for 6.5 or 6 hours.

The other bromo alcohols are produced as follows:

29.6 g (0.25 mol) of the corresponding diol are heated together with 80 g (0.48 mol) of hydrobromic acid, 47% strength, 1500 ml of petroleum spirit (bp. 100 to 140 ° C.) at reflux.

The following reaction products were made:

Reaction product

Response time physics !.

Constants

4-bromobutanol- (1)

6.5 hours

Kp ».7

58 to 60 ° C

5-bromopentanol- (1)

6 hours

Kpi) .5

72 to 74 ° C

6-bromohexanol- (1)

1.5 hours

Kp »/)

85 to 87 ° C

7-bromheptanol- (1)

1.5 hours

Kpo. 5

87 to 89 ° C

8-bromooctanol- (l)

1 H.

Kpo.s

110 to 112 ° C

9-bromononanol- (l)

1 H.

Kpo.4

112 to 114 ° C

10-B romdecanol- (1)

30 min.

Kpo. 3

124 to 126 ° C

The reaction products are colorless liquids up to 8-bromooctanol- (l). 9-Bromononanol- (l) and 10-bromdecanol-(l) are white and solid at room temperature. In principle, bromine alcohols with a larger chain length can also be produced by this process. Since these reaction products are all solid, they are purified by recrystallization.

Example 2

Representation of lecithins with a changed phosphorus-nitrogen distance in the polar head:

A. co-bromoalkylphosphoric dichloride:

32 mmol = 30 ml of phosphorus oxythrichloride (freshly distilled, bp: 105 to 107 ° C) in

70 ml absolute chloroform (distilled 90 min. With circulation over P2O5)

are placed in a round bottom flask. At room temperature, nitrogen is briefly introduced into the solution to displace air. The flask is fitted with a dropping funnel and sealed airtight. While stirring with a magnetic stirrer, 20 mmol of the desired chain length in 50 ml of absolute chloroform are slowly added dropwise at room temperature with exclusion of moisture. The mixture is stirred for about 12 hours. The hydrogen chloride formed in the reaction and excess phosphorus oxytrichloride and chloroform are removed at 30 ° C. on a rotary evaporator. To remove the last traces of phosphorus oxytrichloride, toluene is added and also removed.

The conversion is 95 to 100% and can be followed by thin layer chromatography.

B. Phosphorylation:

The co-bromoalkylphosphoric dichloride obtained according to A. is taken up in 60 ml of absolute chloroform and cooled to 0 ° C. While stirring with a magnetic stirrer, 10 ml of triethylamine (dried over lithium aluminum hydride and freshly distilled) are added. 14 mmol of the corresponding diglyceride , e.g.

SN-1,2-dipalmitoylglycerol,

SN-1,2-dimyristoylglycerol,

1,2-dipentadecyl ketone glycerol,

or another of the above-mentioned starting substances in 60 ml of absolute chloroform are slowly added dropwise at 30 to 35 ° C. with stirring with a magnetic stirrer and in the absence of atmospheric moisture.

It is determined by thin-layer chromatography that the reaction proceeds almost completely when added dropwise.

The light yellow solution turns dark brown in the course of the reaction. The mixture is stirred for a further 3 to 5 hours. Then chloroform and triethylamine are removed on a rotary evaporator at 35 ° C. The reaction product is taken up in 100 ml of tetrahydrofuran. 1 M sodium acetate solution of pH 8.4 is then added with stirring until the solution remains slightly alkaline. 100 ml of diisopropyl ether are added to the reaction product hydrolyzed in this way and the mixture is stirred for 1 hour. After phase separation, the mixture is extracted again with 50 ml of ether. The combined ether phases are 1 hour over s

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Sodium carbonate stirred, filtered and then the ether removed on a • rotary evaporator.

The subsequent reactions take place without further purification of this reaction product.

C. Reaction with an amino base:

The reaction product from B. is taken up in 150 ml of butanone for the further conversion to lecithins. If a cephaline is shown, it is dissolved in 50 ml of chloroform and 100 ml of methanol. 100 ml of acetonitrile and 100 ml of an ethanolic or aqueous solution of the corresponding amino base are added.

The reaction vessel is sealed airtight and kept either at 55 ° C for 1 to 6 hours or at room temperature for 5 to 20 hours. The progress of the reaction is monitored by thin layer chromatography. If the necessary reaction time is exceeded, the reaction product decomposes, which is reflected in a sharp reduction in the yield. The volatile constituents of the reaction mixture are then stripped off at 50 ° C. on a rotary evaporator. The residue is taken up in 150 ml of chloroform, mixed with 100 ml of 2% formic acid and 200 ml of methanol and shaken. The reaction product is in the chloroform phase and is treated for neutralization with 100 ml of 0.1 M sodium acetate solution of pH 5.6 and 200 ml of methanol. After another phase separation, the chloroform phase is dried over 10 g of sodium sulfate and then the chloroform is removed on a rotary evaporator.

The crude product thus obtained is purified by column chromatography. For this purpose, a column with a suspension of 100 g of silica gel (Mallinckrodt AR p. A.) In a solvent system made of chloroform: methanol: ammonia

200: 15: 1 filled. The product dissolved in 10 to 15 ml of solvent is added to this column and impurities are first eluted with the above-mentioned system. The reaction product is then eluted with chloroform: methanol: ammonia = 65: 15: 1 or 65: 30: 3. The fractions are checked for purity by thin layer chromatography.

The yields of the analytically pure products are between 10 and 25% of theory, based on the diglycerides used or other corresponding starting substances.

The compounds listed below were prepared, the analytical values being given in each case.

Group 1:

SN-1,2-dipalmitoylglycerol-3-phosphoric acid-5-trimethylaminopentyl ester C43H88NO9P M: 794.15

C H N P

Calculated 65.03% 11.17% 1.76% 3.90%

Found 64.36% 11.04% 1.84% 3.91%

Group 2:

SN-l-palmitoylglycerol-3-phosphoric acid-5-trimethylaminopentyl ester C27H58NO8P M: 537.72

C H N P

Calculated 58.35% 10.52% 2.52% 5.57%

The analytical values obtained matched the calculated values.

Group 3:

l, 2,3,4,5-pentamyristoyl-D-mannitol-6-phosphoric acid-7-tri-methylaminoheptyl ester C92H166NO14P M: 1541.31

C H N P

Calculated 71.69% 10.86% 0.91% 2.01%

The analytical values obtained matched the calculated values.

Group 4:

a) l-Palmitoyl-2-hexadecyl ether glycerol-3-phosphoric acid-9-trimethylaminononyl ester CwHssNOsP M: 836.27

C H N P

Calculated 67.50% 11.81% 1.67% 3.70%

The analytical values obtained matched the calculated values.

b) 1,3-dioctyl ether glycerol-2-phosphoric acid-6-trimethyl-aminohexyl ester C28H62NO7P M: 555.78

C H N P

Calculated 60.51% 11.24% 2.52% 5.57%

The analytical values obtained matched the calculated values.

Group 5:

1,2-dipentadecyl ketone glycerol-3-phosphoric acid-6-trimethylaminohexyl ester C43H90NO7P M: 750.12

C H N P

Calculated 67.25% 11.83% 1.87% 4.13%

Found 67.28% 11.87% 1.82% 4.14%

Group 7:

l-myristoylpropanediol-3-phosphoric acid-4-trimethylamino-butyl ester C24H52NO7P M: 497.65

C H N P

Calculated 57.92% 10.53% 2.81% 6.22%

The analytical values obtained matched the calculated values.

Group 8:

l-tetradecyl ether propanediol-3-phosphoric acid-4-trimethyl-aminobutyl ester C24H54NO6P M: 483.67

C H N P

Calculated 59.60% 11.25% 2.90% 6.40%

The analytical values obtained matched the calculated values.

Group 1 :

SN-1,2-dipalmitoylglycerol-3-phosphoric acid-6-trimethylaminohexyl ester M: 808.18 C44H90NO9P

C H N P

Calculated 65.39% 11.23% 1.73% 3.83%

Found 66.66% 11.45% 1.80% 4.08%

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SN-1,2-dipalmitoylglycerol-3-phosphoric acid-7-trimethyl-

aminoheptyl ester M: 822.20

C-isHwNOP

H

N

Calculated 65.74% 11.28% 1.70% 3.77% Found 64.90% 11.16% 2.02% 4.59%

SN-1,2-DipalmitoyIgIycerin-3-phosphoric acid-8-trimethyI-

amino octyl ester M: 836.23

C-if, H «NO <; P

H

N

Calculated 66.39% 11.38% 1.65% 3.64%

Found 66.28% 11.43% 1.85% 3.85%

Group 5:

l, 2-DipentadecyIketonglycerin-3-phosphoric acid-5-trimethyl-

aminopentyl ester M: 736.11

C42H88NO7P

H

N

Calculated 66.90% 11.78% 1.90% 4.21%

H

N

Calculated 66.07% 11.33% 1.68% 3.70% Found: 64.15% 10.91% 2.30% 4.60%

SN-1,2-dipalmitoylglycerol-3-phosphoric acid-9-trimethyl-

aminononyl ester M: 850.26

C47H <X, NOP

l, 2-DipentadecyIketongIycerin-3-phosphoric acid-8-trimethylaminooctyl ester M: 778.19 C45HMNO7P

C.

H

N

Calculated 67.91% 11.92% 1.80% 3.98% Found: 68.21% 11.93% 1.89% 3.95%

B

Claims (14)

615 191 1. A process for the preparation of synthetic phospholipids, characterized in that A) a polyhydroxy compound in which one hydroxy group is present in free form and the rest are protected, with a ro-haloalkylphosphoric dichloride of the formula I. Cl O xP-0-Alk-X (I), where X is fluorine, chlorine, bromine or iodine and alk is an alkyl or cycloalkyl radical having at least 3 carbon atoms; and B) the reaction product obtained with an amine of the formula II R1 N ~~~ Rz (II), X R3 wherein R 1, R 2 and R 3 independently of one another denote hydrogen or methyl groups. 2. The method according to claim 1, characterized in that one carries out process step A in the presence of an inert solvent. 2nd PATENT CLAIMS 3. The method according to claim 1, characterized in that one carries out process stage A with the exclusion of moisture. 4. The method according to claim 1, characterized in that one carries out process stage A in the presence of a base. 5. The method according to claim 1, characterized in that phospholipids with a phosphorus-nitrogen grouping of the formula - P — O —Alk - N RZ manufactures. 6. The method according to claim 1, characterized in that one produces SN-1, 2-dipalmitoylglycerol-3-phosphoric acid-5-trimethylaminopentyl ester. 7. The method according to claim 1, characterized in that one produces SN-1-palmitoylglycerol-3-phosphoric acid-5-trimethylaminopentyl ester. 8. The method according to claim 1, characterized in that 1,2,3,4,5-pentamyristoyl-D-mannitol-6-phosphoric acid-7-trimethylaminoheptyl ester is prepared. 9. The method according to claim 1, characterized in that l-palmitoyl-2-hexadecyläthergIycerin-3-phos-phosphoric acid-9-trimethylaminononyl ester is prepared. 10. The method according to claim 1, characterized in that 1, 3-dioctyl ether glycerol-2-phosphoric acid-6-trimethylaminohexyl ester is prepared. 11. The method according to claim 1, characterized in that 1,2-dipentadecylketone glycerol-3-phosphoric acid-6-trimethylaminohexyl ester is prepared. 12. The method according to claim 1, characterized in that one produces l-myristoyl-propanediol-3-phosphoric acid-4-trimethylaminobutyl ester. 13. The method according to claim 1, characterized in that l-tetradecyl ether-propanediol-3-phosphoric acid-4-trimethylaminobutyl ester is produced. 14. Use of synthetic phospholipids produced by the process according to claim 1 as emulsifiers instead of natural phospholipids.