CH619962A5 - Process for the preparation of synthetic alkyl esters of phosphatidic acids and their structural analogues. - Google Patents

Description

The invention relates to the process defined in claim 1 and the conversion of the alkyl esters of the formulas III or IV prepared by this process into the corresponding lyso compounds by the process according to claim 5.

H2C-OH 20 I.

H2C-O-CO-R2

I.

H2C-O-PO-O-R3 25 OH

H2C-0-C0-R1

I.

30 HC-OH

I.

H2C-O-PO-O-R3

I.

OH

35

H2C-OH

I.

HC-O-PO-O-R3

I (XX)

OH

H2C-OH

I.

HC-O-PO-O-R3

I (XX)

OH

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If the radicals R 1 and R 2 are substituted by cycloalkyl groups, those with, for example, 4 to 8, preferably 5, 6 or 7, carbon atoms are suitable for this purpose. Suitable aromatic substituents are, for example, phenyl or naphthyl, which in turn can be substituted.

For R3 there are, for example, alkyl groups with 1 to 23.1 to 21, 1 to 18, 1 to 16, 3 to 25, 3 to 23, 3 to 21, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 3 to 10.4 to 25.4 to 21.4 to 18.4 to 16.4 to 12.6 to 25.6 to 18 or 6 to 14 carbon atoms. The rest R3 can also contain one or more double or triple bonds. Halogen substituents are bromine, chlorine, iodine or fluorine. If the radical R3 carries one or more cycloalkyl groups as substituents, these can have 4 to 8, preferably 5 to 7, carbon atoms. Unsubstituted or substituted phenyl and naphthyl are particularly suitable as aromatic substituents of the radical R3.

When carrying out the method according to claim 1, it is expedient to proceed as follows:

In the reaction in stage A, halogenated hydrocarbons, for. B. chloroform or carbon tetrachloride. This reaction is expediently carried out without the addition of a base, the molar ratio of alcohol of the formula I to phosphorus oxychloride generally being 1: 2 and, of course, being able to vary within certain limits. One mole of alcohol of the formula I can also be reacted with 1.7 to 2.3 moles of phosphorus oxychloride. The reaction is generally carried out under anhydrous conditions. The reaction is expediently carried out at room temperature. However, you can also work at temperatures from -10 to + 80 ° C, for example from 20 to 40 ° C. The reaction time depends on the temperature used and is generally in the range from V2 hours to 15 hours. If one works at room temperature, the reaction time is generally 10 to 12 hours.

After completion of this reaction, which can be followed by thin-layer chromatography, any unconverted phosphorus oxychloride still present and hydrochloric acid formed in excess are expediently removed at, for example, 30 to 35 ° C. in a water jet vacuum. The residue left is the alkylphosphoric dichloride of the formula II. This can be used directly and without further purification for the reaction with the polyhydroxy compound. However, it is not necessary to purify the compound of the formula II by distillation, which is a significant advantage over known phosphorylation processes, since numerous alkylphosphoric dichlorides tend to explode.

The compound of formula II prepared in stage A is very reactive and reacts very easily with the polyhydroxy compounds used in stage B. The reaction in stage B is preferably carried out with exclusion of moisture in an inert organic solvent, for example a chlorinated hydrocarbon such as chloroform or carbon tetrachloride. Other organic solvents, e.g. B. toluene, xylene or benzene. Absolute solvents are preferably used. In addition, it is advantageous in the presence of an organic base, e.g. B. triethylamine to work.

The reaction in stage B can be carried out within a wide temperature range, for example at temperatures from -10 to + 50 ° C. However, the reaction is preferably carried out at room temperature. The reaction time depends on the reaction temperature used and is generally V2 hours to 5 or 6 hours.

The starting substances that can be used in the individual cases can be used both in the form of the racemates and the optically active compounds. The starting materials to be used for the above-mentioned groups of compounds will be listed below.

Suitable starting materials for the preparation of compounds of the formulas III and IV are 1,2- or 1,3-diglycerides with saturated or unsaturated, branched or straight-chain fatty acids, which can be substituted in the manner indicated for R 1 and R 2.

For the preparation of the compounds of group a), acylated sugar alcohols which have a free hydroxyl group are suitable.

Suitable starting compounds for the products of group b) are the corresponding 1,2- and 1,3-dialkylglycerol ethers or acylglyceryl alkyl ethers. The alkyl radicals in these compounds correspond to R 1 and R 2 and can be substituted in the manner given there.

Suitable starting materials for the preparation of the compounds of group d) are the corresponding 1,2- and 1,3-cycloalkylketone glycerols, which can be obtained from glycerol or 2-benzylglycerol by reaction with the cycloalkanone in question.

Monoacylalkanediols are preferred as starting materials for the preparation of the compounds of group e). These alkanediols can be saturated or unsaturated, straight-chain or branched and can be substituted in the manner indicated for R 1 and R 2.

The starting compounds required for the preparation of the group f) compounds are known compounds and can be prepared by processes known from the literature (cf. A.J. Slotboom and P.P.N. Bonsen in Chem. Phys. Liquids [1970], pp. 301 to 398).

When carrying out the method according to claim 5, the cleavage of the groups Ri — CO— or R2 — CO— can be carried out enzymatically with phospholipases Ai and A2.

The lyso compounds of the formulas XVIII to XXI can also be obtained starting from l-acyl-2-benzylglycerols or 1-benzyl-2-acylglycerols. In this case, after phosphorylation has been carried out, catalytic debenzylation is carried out. If protective groups are present in the case of unsaturated fatty acids, these can be removed by mild acid hydrolysis.

The following preferred compounds can be prepared according to the invention:

sn-1,2-dimyristoylglycerol-3-phosphoric acid methyl ester; sn-1 -myristoylglycerol-3-phosphoric acid methyl ester; l, 2,3,4,5-pentapalmitoyl-D-mannitol-6-phosphoric acid butyl ester;

(3) -β-bromoethyl glycerol dioctyl ether phosphoric acid; Diheptadecylketone glycerol-3-phosphoric acid octyl ester; Cyclopentadecyl ketone glycerol-3-phosphoric acid-β-bromo-ethyl ester;

01eoylhexanediol- (1,6) -phosphoric acid isopropyl ester; Propanediol (1,3) hexadecyl ether phosphoric acid hexyl ester.

Of the salts of the compounds obtainable according to the invention, the sodium salts are preferred.

The compounds obtainable according to the invention, in particular those of the formulas III to VI, have valuable pharmacological properties. These compounds are highly surface-active and, due to their structural similarity to the phospholipids found in the cell membranes, can influence the interfacial activity of these membranes. Due to their nega-

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tive charge can also affect the charge of biological membranes. Because of these properties, it can be expected that these substances will change the effectiveness of pharmaceuticals by increasing their resorbability and influencing their distribution in the organism. Accordingly, these compounds are valuable additives for the manufacture of drugs.

The compounds obtainable according to the invention, in particular the compounds of the formulas III to VI, are easily dispersible in water and form stable emulsions over a large pH. It is surprising that these emulsions are still stable even at pH 1.0, while, for example, emulsions of lecithin already flocculate at a pH of 2.0. Dispersions of the compounds mentioned are therefore suitable for passing through the stomach unchanged (pH 1.5) and for example improving the resorbability of fats.

The compounds obtainable according to the invention, in particular those of the formulas VII and VIII, are highly surface-active and have lyrical activity with respect to natural membranes (e.g. erythrocytes). They can therefore be used in a variety of ways to lyse these membranes or in sublytic doses to change the membrane properties, which can also influence the effectiveness of pharmaceuticals.

The compounds obtainable according to the invention generally have very good emulsifying properties. Since they have a similar structure to the corresponding natural products, they are nutritionally harmless and can therefore be used in many ways as additives for food. If these compounds are added to margarine, for example, a better water binding is achieved, which prevents splashing in the pan and gives the margarine butter-like properties when roasted. The compounds obtainable according to the invention can also be used in fresh water to emulsify syrup and fat and at the same time prevent the fat from becoming rancid. In addition, the compounds obtainable according to the invention can be used in the production of cosmetics, detergents and soaps, even small additions improving the suppleness and absorbability of ointments, creams, toothpaste and soaps.

The following examples serve to explain the invention.

example 1

General representation of the alkylphosphoric dichlorides:

80 g (0.6 mol) of POCb (freshly distilled, bp. 105 to 107 ° C) in 100 ml of absolute chloroform (distilled for 90 min with circulation over P2O5) are placed in a three-necked flask with a condenser, dropping funnel and nitrogen inlet tube. Nitrogen is slowly introduced while stirring with a magnetic stirrer and 0.3 mol of the alcohol in question in 50 ml of absolute chloroform are added dropwise. The mixture is stirred for 12 hours at room temperature and then the hydrogen chloride formed, excess POCb and chloroform are removed on a rotary evaporator at 30 ° C. To remove the last traces of POCb, 50 ml of toluene are added and also removed.

The remaining oil, the alkylphosphoric dichloride, can be reacted further without purification. Distillation was carried out for some low boiling alkyl phosphoric acid dichlorides. The following boiling points were observed:

CH3-O-PO-CI2 C2H5-O-PO-CI2 C3H7-O-PO-CI2 C4H9-O-PO-CI2

KpiOr

The conversion is 90 to 100% and can be followed by thin layer chromatography.

Example 2

s Representation of co-bromoalkylphosphoric dichlorides:

a) Preparation of bromoalcohols of different chain lengths using a simplified procedure:

10 compounds of the formula

Br- (CH2) n-OH with n = 4bis10

15

were synthesized.

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.

The diol and hydrobromic acid are placed in a round bottom flask. The starting products are overlaid with petroleum spirit or benzene / petroleum spirit. 25 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-bromobutanol- (l) and 5-bromopentanol- (l) are shown as follows:

40

0.25 mol = 22.5 g 1,4-butanediol or 26 g 1,5-pentadiol, 4S 0.48 mol = 80 g HBr 47%,

500 ml of benzene and 50 ml of petroleum spirit, bp 100 to 140 ° C

are heated under reflux for 6.5 or 6 hours.

50

The other bromoalcohols are shown as follows:

0.25 mol = 29.6 g 1,6-hexanediol or corresponding diol, ss 0.48 mol = 80 g HBr 47%,

1500 ml petroleum spirit, bp 100 to 140 ° C

are heated under reflux.

44 to 47 ° C 54 to 56 ° C 66 to 68 ° C 85 to 87 ° C

60

65

Reaction product

Response time

Physical. Constants

4-bromobutanol (l) 6.5 h

5-bromopentanol- (l) 6 h

6-bromohexanol- (l) 1.5 hours

7-bromheptanol- (l) 1.5 hours

8-bromooctanol- (l) 1 h

9-Bromononanol- (1) 1 hour 10-Bromodecanol- (1) 30 minutes

KPo, 7 58 to 60 ° C Kpo, 5 72 to 74 ° C Kpo.e 85 to 87 ° C Kpo, s 87 to 89 ° C Kpo.s 110 to 112 ° C Kpo, 4 112 to 114 ° C Kpo, 3124 to 126 ° C

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6

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.

b) Preparation of co-bromoalkylphosphoric dichloride: 32 mmol = 30 ml of phosphorus oxytrichloride (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.

Example 3

General representation of the alkyl esters of phosphatidic acid and structural analogues:

The phosphorylating agent from Example 1 or from Example 2 (0.3 mol) is dissolved in 100 ml of absolute chloroform (distilled for 90 min with circulation over P2O5) and cooled to 0 to 5 ° C. with an ice bath. While stirring with a magnetic stirrer, 60 g (0.6 mol) of absolute triethylamine (dried over lithium aluminum hydride and freshly distilled) in 50 ml of absolute chloroform are added dropwise. The ice bath is now replaced by a water bath at 20 ° C. The corresponding starting substance, 0.15 mol, dissolved in 150 ml of absolute chloroform, is added dropwise to the phosphorylation mixture with constant stirring.

It is determined by thin layer chromatography that the reaction is practically complete after the dropwise addition. After a further 6 hours at 40 ° C., the reaction mixture is freed from solvent on a rotary evaporator at 35 ° C. and the residue is taken up in 450 ml of tetrahydrofuran. While stirring, IM sodium acetate solution of pH 8.4 is added to the suspension or solution of the reaction mixture in tetrahydrofuran until the water phase remains neutral (pH approx. 7). To do this, approx. 450 ml IM sodium acetate solution must be added. The hydrolyzed reaction product is extracted as the sodium salt with 450 ml of diisopropyl ether. The water phase is extracted again with 200 ml of diisopropyl ether. The combined diisopropyl ether extracts are mixed with stirring with 10 g of sodium carbonate to remove water and to ensure complete conversion of the reaction product into the sodium salt.

When preparing derivatives with less than 14 carbon atoms in total, the reaction solution is acidified with HCl before extraction with diisopropyl ether, pH approx. 2. The very short-chain derivatives are better extracted as free acids and can be crystallized out by careful addition of sodium methylate in methanol will.

The diisopropyl ether phase is filtered and the filtrate evaporated in vacuo. The residue is recrystallized from ethyl methyl ketone / acetone mixtures. The reaction products obtained are generally pure for analysis. Otherwise, chromatography on silica gel is carried out to completely purify the products. The yields of pure analytical product varied between 70 and 90% (based on the starting products used).

The following connections were made:

Group 1 connection:

sn-l, 2-dimyristoylglycerol-3-phosphoric acid methyl ester, as sodium salt, C32H «2NaOsP (628.8)

calculated: C 61.12% H 9.94% P 4.93%

The values found match the calculated values.

Group 2 connection:

sn-l-myristoylglycerol-3-phosphoric acid methyl ester, as sodium salt, Ci8H36Na07P (418.5)

calculated: C 51.67% H 8.67% P 7.40%

The values found match the calculated values.

Group 3 connection:

l, 2,3,4,5-pentapalmitoyl-D-mannitol-6-phosphoric acid butyl

ester, as sodium salt, C9oHi72NaOi4P (1532.3)

calculated: C 70.55% H 11.32% P 2.02%

The values found match the calculated values.

Group 4 connection:

Glycerol dioctyl ether phosphoric acid (3) -ß-bromoethyl ester, as sodium salt, C2iH43BrNaOßP (525.5)

calculated: C 48.00% H 8.25% Br 15.21% P 5.90%

The values found match the calculated values.

Group 5 connection:

Diheptadecylketone glycerol-3-phosphoric acid octyl ester, as sodium salt, Gt6H92Na06P (795.21)

calculated: C 69.48% H 11.66% P 3.90%

The values found match the calculated values.

Group 6 connection:

Cyclopentadecylketone glycerol-3-phosphoric acid-β-bromoethyl ester, as sodium salt, C2oH37BrNaP (484.4)

calculated: C 49.59% H 7.70% Br 16.49% P 6.39%

The values found match the calculated values.

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Group 7 connection:

01eoylhexanediol- (1,6) -phosphoric acid isopropyl ester, as sodium salt, C27H52NaOtìP (526.68)

calculated: C 61.57% H 9.52% P 5.88%

The values found match the calculated values.

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Group 8 connection:

Propanediol (1,3) -hexadecyl ether phosphoric acid hexyl ester, as sodium salt, C25H52NaOsP (486.7)

s calculated: C 61.70% H 10.77% P 6.37%

The values found match the calculated values.

B

Claims (10)

619962 PATENT CLAIMS 1. Process for the preparation of synthetic alkyl esters of phosphatidic acids according to formula III or IV H2C-O-CO-R1 I. HC-O-CO-R2 me (in) 0-P0-0-R3 I. OH H2C-O-CO-R1 I. HC-O-PO-O-R3 (IV), I. OH H2C-O-CO-R2 wherein R 1 and R 2 are saturated or unsaturated straight-chain or branched alkyl groups having 5 to 25 carbon atoms, the alkyl groups optionally being substituted by one or more halogen atoms or a cycloalkyl group or by an aromatic ring; and R3 represents a saturated or unsaturated straight-chain or branched alkyl group having 1 to 25 carbon atoms, which may be substituted by halogen, one or more cycloalkyl groups or one or more aromatic groups, and their structural analogs, which include the following groups of compounds, a) Analogues with sugar according to the formula V H2C-O-CO-R I. (HC — O-CO-R) * (V), H2C-O-PO-O-R3 I. OH wherein x is zero or an integer from 1 to 5 and R has the same meaning as given for Ri and R2; b) ether analogs of the compounds of the formulas III and IV and ether / ester analogs of compounds of the formula V corresponding to the formulas VI or VII H2C-O-R1 I. HC-O-R2 I (VI) H2C-O-PO-O-R3 I. OH c) alkyl dialkyl ketone glycerol phosphoric ester corresponding to formulas VIII and IX H2C-Ov RJ V HC-O H2C-O-PO-O-R3 OH (VIII) IS 20th (IX); H2C-O> Ri C. HC-0 /// ^ H H2C-O-PO-O-R3 i OH d) Cycloalkylketonglycerinphosphorsäurealkylester according to the formulas X and XI (ÇH2) y (X) 40 45 mc-o ^ I (ÇH2) v HC-O // V ^ 7 (XI), H2C-CA> 0-0-R3 I. OH wherein y is an integer from 5 to 32; e) alkyl esters of deoxylysophosphatidic acids corresponding to the formulas XII, XIII and XIV so H2C-O-CO-R1 I. (CH2) m I. H2C-O-PO-O-R3 OH (XII) H2C-O-R1 HC-O-PO-O-Rs I. OH H2C O-R2 (VII); «0 HsC I. (CH2) m I. HC-O-CO-Ri H2C-O-PO-O-R3 I. OH 6S (XIII) 2. The method according to claim 1, characterized in that one works in process stage B in the presence of an inert organic solvent. 3. The method according to claim 1 or 2, characterized 3rd 619 962 H3C (CH2) p HC-O-CO-Ri (XIV) I. (CH2) q H2C-O-PO-O-R3 I. OH wherein m is zero or an integer from 1 to 14 and the sum of p + q = m; f) ether analogs of the compounds mentioned under e) according to the formulas XV, XVI and XVII H2C-O-R1 I. (CH2) m I (XV) H2C-O-PO-O-R3 I. OH (CH2) m-CH3 I. HC-O-Ri I (XVI) H2C-0-P0-0-R3 I. OH (CH2) p-CH3 HC-O-Ri I. (CH2) q (XVII) I. H2C-O-PO-O-R3 I. OH where m, p and q have the meaning given under e), and of their physiologically tolerable salts, characterized in that one A) a primary alcohol of the formula I R3-OH (I) reacted with phosphorus oxychloride in the presence of an inert organic solvent; and B) the phosphorylating agent of the formula II obtained Cl NXs> P-OR3 (II) XII Cl O with a corresponding polyhydroxy compound in which one hydroxy group is present in free form and the others are protected. 4. The method according to claim 1, characterized in that the process products in their physiological 10 compatible salts transferred. 5. The method according to claim 1, characterized in that a compound of the formula III or IV, in which the alkyl groups R 1 and R 2 have 5 to 21.5 to 18 or 5 to 16 carbon atoms, is prepared. ls 6. Process for the preparation of lyso compounds of the alkyl esters of phosphatidic acids of the formula III and IV according to the formulas XVIII to XXI (XVIII) (XIX) H2C-O-CO-R1 I. HC-O-PO-O-R3 I (XXI) OH H2C-O-CO-R2 H2C-OH 45 characterized in that a compound of the formula III or IV is prepared by the process according to claim 1 and the groups Ri — CO - or R2-CO- are split off therefrom. 5 characterized in that one works in process stage B in the presence of an organic base and with exclusion of moisture. 7. alkyl esters of phosphatidic acids and their Strukturana-50 Ioga of groups a) to f), prepared by the process according to claim 1. 8. Lyso compounds of the formulas XVIII to XXI, prepared by the process according to claim 6. 9. Use of the alkyl esters according to claim 7 as 55 emulsifiers instead of the corresponding natural phos- pholipid. 10. Use of the lyso compounds according to claim 8 as emulsifiers instead of the corresponding natural phospholipids.