SYNTHETIC ALKYL ESTERS OF PHOSPHOLIPID ACID, STRUCTURAL ANALOGS THEREOF AND A PROCESS FOR THEIR MANUFACTURE AND THEIR USE

ESTERS SYNTHETIQUES ALKYLIQUES DE L'ACIDE PHOSPHOLIPIDE, LEURS ANALOGUES STRUCTURALS, PROCEDE POUR LEUR FABRICATION ET LEURS UTILISATIONS

English Abstract

SYNTHETIC ALKYL ESTERS OF PHOSPHOLIPID ACID, STRUCTURAL ANALOGS
THEREOF AND A PROCESS FOR THEIR MANUFACTURE AND THEIR USE
Abstract of the Disclosure:
Synthetic alkylesters of phospholipid acid, the structu-
ral analogues thereof, their physiologically acceptable salts
as well as a process for preparing them and their use.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a synthetic alkyl-
ester of phospholipic acid, the structural analogues thereof
and the physiologically acceptable salts thereof in which
(A) a primary alcohol of the formula
R3OH
wherein R3 represents a saturated or unsaturated straight-
chain or branched alkyl group of 1 to 25 carbon atoms,
which may also be substituted by halogen, one or more cyclo-
alkyl groups or one or more aromatic groups, is reacted
with phosphorus oxychloride in the presence of an inert
organic solvent, and
(B) the resulting phosphorylation agent of the formula
<IMG>
wherein R3 is as defined above, is reacted with a polyhydroxy
compound, having up to 17 carbon atoms, having a free hydroxy
group and the other hydroxy groups of which are protected,
and,
to produce a salt, the product may be reacted with a physiologi-
cally acceptable reactant.
2. A process as claimed in claim 1, in which reaction
(B) is carried out in the presence of an inert organic solvent.
3. A process as claimed in claim 1, in which reaction
(B) is carried out in the presence of an organic base and with

the exclusion of moisture.
4. A synthetic alkylester of phospholipid acid, the
structural analogues and physiologically acceptable salts thereof,
whenever obtained according to a process as claimed in claim 1,
claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which in reaction
(A) the solvent is selected from the group of chloroform and
carbon tetrachloride.
6. A process as claimed in claim 1 in which in reaction
(A) the molar ratio of alcohol to phosphorus oxychloride is in
the range of from about 1:2.
7. A process as claimed in claim 1 in which reaction (A)
is carried out under anhydrous conditions and at a temperature
in the range of from -10 to +80°C.
8. A synthetic alkylester of phospholipid acid, the
structural analogues and physiologically acceptable salts there-
of, whenever obtained according to a process as claimed in claim
5, claim 6 or claim 7 or by an obvious chemical equivalent there-
of.
9. A process as claimed in claim 1 for the preparation
of an alkyl ester of phospholipid acid of the formula
<IMG>
21

wherein R1 and R2 are identical or different and each represents
a substituted or unsubstituted alkyl group having 5 to 25 car-
baon atoms, and R3 is as defined in claim 1, the structural ana-
longues thereof and the physiologically acceptable salts there-
of in which
(A) a primary alcohol of the formula R3OH wherein R3 is as de-
fined in claim 1, is reacted with phosphorus-oxychloride
in an inert organic solvent, and
(B) the resulting phosphorylation agent is reacted with a poly-
hydroxy compound having a free hydroxy group and the addi-
tional hydroxy groups are protected and, to product a salt,
the product may be reacted with a physiologically accept-
able reactant.
10. An alkyl ester of phospholipid acid of the struc-
tural formula as set forth in claim 9, whenever obtained ac-
cording to a process as claimed in claim 9 or by an obvious
chemical equivalent thereof.
11. A process as claimed in claim 1 for the preparation
of sn-1,2-dimyristoylglycerol-3-phosphoric acid methylester in
which methanol is reacted with phosphorus oxychloride in an
inert organic solvent, the resultant methyl-phosphoric-acid-
dichloride is reacted with 1,2-dimyristoyl-sn-glycerol in the
presence of a base and the resultant product is subsequently
isolated.
12. sn-1,2-Dimyristoylglycerol-3-phosphoric acid methyl-
ester, whenever obtained according to a process as claimed in
claim 11 or by an obvious chemical equivalent thereof.
22

13. A process as claimed in claim 1 for the preparation
of sn-1-myristoylglycerol-3-phosphoric acid methylester in
which methanol is reacted with phosphorus oxychloride in an
inert organic solvent, the resultant methyl-phosphoric-acid-
dichloride is reacted with 1-myristoyl-2-benzene-sn-glycerol
in the presence of a base and the resultant product is subse-
quently isolated.
14. sn-1-Myristoylglycerol-3-phosphoric acid methylester,
whenever obtained according to a process as claimed in claim
13 or by an obivous chemical equivalent thereof.
15. A process as claimed in claim 1 for the preparation
of 1,2,3,4,5-pentapalmitoyl-D-mannitol-6-phosphoric acid butyl-
ester in which butanol is reacted with phosphorus oxychloride
in an inert organic solvent, the resultant butyl-phosphoric-
acid-dichloride is reacted with 1,2,3,4,5-pentapalmitoyl-D-
mannitol in the presence of a base and the resultant product
is isolated.
16. 1,2,3,4,5-Pentapalmitoyl-D-mannitol-6-phosphoric
acid butyl-ester, whenever obtained according to a process as
claimed in claim 15 or by an obvious chemical equivalent there-
of.
17. A process as claimed in claim 1 for the preparation
of glycerol dioctyl ether phosphoric acid-(3)-.beta.-bromoethylester
in which bromoethyl alcohol is reacted with phosphorus oxychlor-
ide in an inert organic solvent, the resultant bromoethyl-phos-
phoric-acid-dichloride is reacted with 1,2-dioctyl-glycerol
in the presence of a base and the product is subsequently isolated.
23

18. Glycerol dioctyl ether phosphoric acid-(3)-.beta.-bromo-
ethylester, whenever obtained according to a process as claimed
in claim 17 or by an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 for the preparation
of diheptadecyl ketoneglycerol-3-phosphoric acid octylester
in which octanol is reacted with phosphorus oxychloride in an
inert organic solvent, the resultant octyl-phosphoric-acid-
dichloride is reacted with 1,2-diheptadecylketone-glycerol in
the presence of a base and the product is subsequently isolated.
20. Diheptadecyl ketoneglycerol-3-phosphoric acid octy-
ester, whenever obtained according to a process as claimed in
claim 19 or by an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 for the preparation
of cyclopentadecyl ketoneglycerol-3-phosphoric acid-.beta.-bromoethyl-
ester in which .beta.-bromoethanol is reacted with phosphorus oxy-
chloride in an inert organic solvent, the result .beta.-bromoethyl-
phosphoric acid-dichloride is reacted with cyclopentadecylketone-
glycerol in the presence of a base and the product is subsequently
isolated.
22. Cyclopentadecyl ketoneglycerol-3-phosphoric acid-.beta.-
bromoethyl-ester, whenever obtained according to a process as
claimed in claim 21 or by an obvious chemical equivalent there-
of.
23. A process as claimed in claim 1 for the preparation
of oleoyl-hexanediol-(1,6)-phosphoric acid isopropylester in
which isopropyl alcohol is reacted with phosphorus oxychloride
24

in an inert organic solvent, the resultant isopropyl-phosphoric-
acid-dichloride is reacted with 1-oleoyl-hexanediol-(1,6) in
the presence of a base and the product is subsequently isolated.
24. Oleoyl-hexanediol-(1,6)-phosphoric acid isopropyl-
ester, whenever obtained according to a process as claimed in
claim 23 or by an obvious chemical equivalent thereof.
25. A process as claimed in claim 1 for the preparation
of propanediol-(1,3)-hexadecylether phosphoric acid hexylester
in which hexanol is reacted with phosphorus oxychloride in an
inert organic solvent, the resultant hexyl-phosphoric-acid-di-
chloride is reacted with 1-hexadecyl-propanediol-(1,3) in the
presence of a base and the resultant product is subsequently
isolated.
26. Propanediol-(1,3)-hexadecylether phosphoric acid
hexylester, whenever obtained according to a process as claimed
in claim 25 or by an obvious chemical equivalent thereof.

Description

HOE 74/B 036 ~ ~
~63:131
The present invention relates to synthetic alkyl esters of
phospholipid acid, the structural analogs and the physiologi-
cally acceptable salts thereof and to a process for their manu-
facture.
The process of the invention comprises
A) reacting a primary alcohol of the formula
R30H
wherein R3 stands for a saturated or unsaturated straight-
chain or branched alkyl group of one to 25 carbon atoms,
which may be substituted by halogen, a cycloalkyl group or
an aromatic group, with phosphorus oxychloride in the presence
of an inert organic solvent, and
B) reacting the resulting phosphorylation agent oE the ormula
Cl \
/ PO - OR3 II
wherein R3 is defined as above, with a polyhydroxy compound
hauing a free hydroxy group and the further hydroxy groups
of which are protected.
The process of the present invention permits the preparation
of large numbers of alkyl esters of phospholipid acid by simply
reacting a primary alcohol with phosphorus oxychloride. The
resulting phosphorylation agent of formula II may be reacted
directly without isolation with the polyhydroxy compound without
having to distil the phosphorylation agent.
In the above formula I, R3 may stand for a saturated or un-
saturated straight-chain or branched alkyl group having 1 to 25
carbon atoms, for example 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,
.~ - 2 - ~
: . . .. ,. :: .. . ., : ,, ,,, ,, ............... : .. : -.~
. . ~ . ::. , . : : ~ .: .

~063131 liOE 74/~ 036
3 to 10, 4 to 25, 4 to 21, 4 to 18, 4 to 1~, 4 to 12, 6 to 25,
6 to 18 or 6 to 14 carbon atoms.
The group represented by R3 may contain one or more double
bonds or triple bonds and may be substituted by halogen, such as
bromine, chlorine, iodine or fluorine. It may also be substituted
by one or more cycloalkyl groups having 4 to 8, preferably 5 to
7, carbon atoms, or by 1 or more aromatic groups, such as phenyl
or naphthyl groups or substituted phenyl groups. The reaction of
the primary alcohol with the phosphorus oxychloride yields the
phosphorylation agent of the general formula II.
The reaction of the primary alcohol with phosphorus oxy-
chloride is carried out in the presence of an inert organic sol-
vent, for example halogenated hydrocarbons, such as chloroform
or carbon tetrachloride. The reaction is carried out without
adding a base. The molar ratio of alcohol to phosphorus oxy
chloride is generally 1:2, but it may of course b~ varied within ;
certain limits. For example, 1 mol of alcohol may be reacted with ;~
1.7 to 2.3 mols of phosphorus oxychloride. The reaction is
generally carried out under anhydrous conditions. The reaction
temperature is generally room temperature but temperatures of
-10 to ~80C, for example from 20C to ~0C, may also be applied.
The reaction time depends on the temperature chosen and ranges
from half an hour to 15 hours generally from 10 to 12 hourst when
room temperature is applied. ~
When the reaction which can be controlled by thin-layer ;;
chromatography is complete excess phosphorus oxychloride and
excess hydrochloric acid may be eliminated in a hydrogen vacuum,
for example at 30 to 35C. The alkyl phosphoric aci~ dichloride
remains as a residue. This alkyl phosphoric acid dichloxide may
--

~63~3~ HOE 74/B 036
directly be used for the phosphorylation reaction without further
purification. A distillation is not necessary. Compared to known
phosphorylation methods, this is a substantial advantage since
many alkyl phosphoric acid dichlorides tend to decompose in an
explosive manner.
The phosphorylation agent of the general formula II is very
reactive and reacts with a large number of polyhydroxy compounds
containing a free hydroxy group. The reaction 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, such as toluene or xylene
or benzene may also be used; absolute solvents are however pre-
ferred.
The reaction of the phosphorylation agent with the poly-
hydroxy compound may be carried out within a wide range of -
temperature, for example from -10C to +50C, preferably at room
temperature. The reaction time used depends on the reaction tem-
perature chosen, it ranges generally from half an hour to 5 or
6 hours. The phosphorylation reaction is preferably carried out
in the presence of a base, for example of triethyl amine.
The phosphorylation agent obtained according to this in-
vention allows a number of alkyl esters of phospholipid acid to
be obtained. As polyhydroxy compounds, any polyhydroxy compounds
may be used which contain a free hydroxy group and the other
hydroxy groups of which are protected, for example by esteri-
fication, e~herification, acetal- or ketal formation. In general,
the polyhydroxy compound used is a glyceride or a correspondingly
higher homolog. It is thus possible according to the invention
to phosphorylate erythritol, pentitol or hexitol derivatives but
-- 4 --
.. .. .. . . .
;: , . : . : . :
,. . . ,
' ! ' -
' : ' ';

~63131 flOE 74/B 036
also cyclic polyhydroxy compounds, such for example as cyclic
saccharic alcohols. Generally, monosaccaride derivatives and
oligo-saccharide derivatives may be ùsed according to the process
of the invention.
The process of the present invention may be carried out us-
ing racemic mixtures of pure optical isomers. The present invention
also provides the products obtained according to the process of
this invention. As already mentioned above, this process yields
a large variety of different alkyl esters of phospholipid acid,
of which individual groups are hereinafter cited as example that
can be prepared according to the process of the invention.
1. Alkyl esters of phospholipid acid
H2C-O-CO-R
Hl- o-cO-R~ III
H2C-O-PO-O-R3
OH ;~
H C - O - CO - R
HC - O - PO - O - R3 IV
¦ OH
~2C - O - CO - R2
In the formulae III and IV, R3 is defined as above. Rl and
R2 each stand for a saturated or unsaturated straight-chain or
branched alkyl group having 5 to 25, 5 to 21 or 5 to 18, 5 to
16 carbon atoms, which may also be substituted by 1 or more, i.e~
2, 3, 4 and more halogen atoms, such as fluorine, chlorine,
bromine or iodine atoms. The alkyl groups may also be substituted
by a cycloalkyl group or an aromatic ring. If the alkyl groups are
substituted by a cycloalkyl group, this may contain 4 to 8, pre-
ferably 5, 6 or 7, carbon atoms. I~ the alkyl groups are sub-
,. ~ , .
- . . , - ., , ~ : . .

~OE 7~/B 036
~63~31
stituted by an aromatic ring, this may for example be a phenyl
ring ox a naphthyl ring which may also carry further substituents.
Starting substances are racemic or optically active 1,2- or
1,3-diglycerides having saturated, unsaturated, branched or halo-
genated fatty acids or fatty acids which contain a cycloalkane or
aromatic ring.
2. Lyso compounds of compounds of Group 1
Starting compounds are l-acyl-2-benzyl glycerols or l-benzyl-
2-acyl glycerols. The phosphorylation reaction provides the lyso
compounds by catalytic debenzylation. Unsaturated compounds are
prepared with the help of protective groups which may be eliminated
by a mild acid hydrolysis.
The starting compounds may also be obtained by biochemical
methods from the compounds of Group 1 by enzymatic splitting with
the phospholipases Al and A2.
3. Analogs with saccharic alcohols
H2C - O - CO - R
(HC - O - CO ~ R)x V
H2C ~
O-PO-O-R3
In the above formula V, R3 is defined as above, and R has
the same meaning as Rl and R2, and X stands for zero or an integer
of from 1 to 5, i.e. 0, 1, 2, 3, 4 or 5.
Starting substances are acylated saccharic alcohols which
contain a free hydroxy group.
4. ~ther analogs of the compounds of Groups 1 to 3 and ether/
ester analogs of the groups of compounds 1 and 3, for example
,, ~.,:,...
- 6 -
..
.

1063131 HOE 74/B 036 ~ ~
H2C -- O - Rl . ~
HC - O - R2 VI
H2C - O - PO - o - R
OH
H2l Rl
HC - O - PO - O ~ R3 VII
I OH
H2C~ ~ ~
In the formulae VI and VII, Rl, R2 and R3 are defined as above.
Starting substances are 1,2- and 1,3-dialkylglycerol ethers
or acylglycerol alkyl ethers. The alkyl radicals may be saturated,
un~aturated, branched or halogenated and may also contain a cyclo-
alkane or an aromatic ring.
5. Dialkyl ketone glycerol_phosphoric acid alkyl esters
H2C - O 1 -
\C / ~ ~
HC - O \ R2 VIII
H2C - O - PO - O - R3
OH -
H2C - o \
¦ C \ IX
HC - O H
H2C - O - IO - O - R
.., . :~
OH ~ -
In the above formulae VIII and IX7 Rl, R2 and R3 are defined
as above.
Starting substances are the 1,2- and 1,3-dialkyl ketone ~-
glycerols or the corresponding acetals which may be obtained from
`' - 7 -

~063~31 HOE 74/B 036
glycerol or 2-benzyl glycerol by reaction with the corresponding
ketones or aldehydes. The ketones or aldehydes may be saturated,
unsaturated, branched or halogenated and ~lay also contain a
cycloalkane or an aromatic ring.
6. Cycloalkyl ketone glycerol phosphoric acid alkyl esters
H C - O
2 \
/C (CH2)y X
HC - O
H2C - O - PO - o - R3
OH
H C - O
2 \ ~,_-----__~
/ (CH2)y XI
HC - O ~
H2C - O IO - O - R3
OH
In the above formulae, R3 is defined as above, and y stands
for an integer of from 5 to 32, for example 5 to 28, 5 to 24,
5 to 18, 5 to 16, 5 to 14, 5 to 12, 5 to 10, 5 to 8.
Starting substances are 1,2- and 1,3-cycloalkyl ketone
glycerols which may be obtained from glycerol or 2-benzylglycerol
by reaction with the corresponding cycloalkanone.
7. Alkyl esters of desoxylyso phospholipid acid
HzC - O - CO - R
(I 2~m XII
H2C - O - IO - o - R3
OH
, ' :
, .
- 8 -
,
.~ .
. . :. ~ , , , . . ~ , . ;
-:
. .
: ~ ~ : . ::: .

1063131 HOE 74/B U36
31 ;
( 2)m ;~
¦ XIII
HC - O - CO - R
H2C - O - 70 - O - R3
OH
H3
( CH2 ) p ' :.
HC - O - CO ~ Rl XIV ~
(fH2) q ~: .
10 H2C - O - lo - o - R3
OH
In the above formulae, Rl and R3 are defined as above, and
m stands for zero or for an integer of rom 1 to 14, for example
for 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and p ~ ~ = m.
15 As starting substances, the monoacylalkane diols are preferred. ~
The alkane diols may be saturated, unsaturated, branched or ~ ;
halogenated and may also contain a cycloalkane or an aromatic ~
ring. ~ ~ ;
8. Ether analogs of compounds of Group 6
Methods for the preparation of the said starting substances
are known (s. publication of A.J. Slotboom and P.P.N.
Bonsen "Chem. Phys. Liquids" (1970), pages 301 to 398).
The compounds of the invention corresponding to formulae
I, III to VI have valuable pharmacological properties and they
are potent surfactants which, owing to their structural analogy
with the phospholipids present in the cell membranes, are able to
influence the surface activity of these membranes. Their
negative charge a~ physiological p~-values is moreover capable
of influencing the charge of biological membranes.
_ g _ ,.
,~ .
: , ~- : -: .:: : . . . . .. ., . :: : , . . .

1063~3~ HOE 74/B 036 ~
Owing to these properties, these substances can be expected
to modify the activity of pharmaceuticals by increasing their
ahsorbability and their distribution in the organism~ The
compounds are valuable additives in the manufacture of drugs.
The compounds of formulae I and III to IV are readily dis-
persible in water and give emulsions which are stable over
a wide pH range. It is surprising that these emulsions are
even still stable at a pH of 1.0 whilst, for example, emulsions
of lecithin precipitate in flakes already at a pH of 2Ø
Dispersions of the said compounds are also suitable to pass
unchanged through the stomach (pH 1.5) and to improve,
for example, the absorbability of fats.
The compounds of formulae II, VII and VIII are potent surfactants
and have a lytic activity on natural membranes (for example
erythrocytes). They may therefore be used in many ways for the
disintegration of these membranes or, when applied in sub-
lytic dosages, for a modification of the properties of
membranes, which again may influence the activity of pharma- ~
ceutical compositions. `
The compounds of the invention generally have very good
emulsifying properties. Having a structure similar to that
of natural products, they are physiologically acceptable
-- 10 --
. . ~, . . , ; . . , . :
. : ........ ' ' . :: ', - . ~ , , . : . ,
,. : ~ , , -: , . , ~::
., : :.
., . . . . , . . - ,

1~63131 HOE 74/B 03Ç
in foodstuffs and may therefore be used for a variety of
applications. ~hen added to margarine, they bring about a
better linkage to water, thus preventing it from splashing
in the frying pan and imparting to it butter like properties
when used for frying. They may be used in sweets for
emulsifying sirup with fat and also prevent: the fat getting -~`
rank. When applied for cosmetic purposes and for the making
of soaps small additives of the products of the invention
improve the suppleness and absorption of ointments, creams,
tooth pastes, soaps and the like.
The following examples illustrate the invention.
Example 1
General preparation of alkylphosphoric acid dichlorides:
80 g (0,6 mol) of POC13 (freshly distilled, boiling point ~-
105 to 107C) in 100 ml of absolute chloroform (distilled
for 90 minutes with circulation over P2O5) were placed
in a three-neck flask equipped with cooler, dropping funnel
and nitrogen inlet tube. While stirring by means of a
magnetically operated stirrer, nitrogen was slowly fed in,
and 0.3 mol of the said alcohol in 50 ml of absolute chloro- ~ -
form was added dropwise. The mixture was stirred for 12 hours ; ~
~ '
-- 1 1 -- ,
.. ...

~06313~ HOE 74/B 036
at room temperature, and the resulting hydrogen chloride,
excess POC13 and chloroform were eliminated at 30C in the
rotary evaporator. To eliminate any trace of POC13, 50 ml
of toluene were added and likewise drained off. ~;
The remaining oily substance, i.e. the alkyl-phosphoric acid
dichloride, can be reacted further without purification.
Distillation was performed on some of low boiling alkyl
phosphoric acid dichlorides and the following boiling points
were observed: boiling point at 10 mm Hg
CH3-O-PO-C12 44 to 47C
C2H5-O-Po C12 54 to 56C
C3H7-O-PO C12 66 to 68C
C H -O-PO-C12 85 to 87C
. .
The reaction provided a yield of 90 to 100~ and can be ~
controlled by thin-layer chromatography. ~ ;`
. ,~
Example 2
.
Preparation of ~-bromoalkyl-phosphoric acid dichlorides:
a) Preparation of bromo alcohols having different chain length
according to a simple process:
Compounds of formula
Br - (CH2)n - OH
in which n stands for the integer of 4 to 10, were synthesized. ;;
- 12 -
:
. ~ .
.. , . . . . . ~ ` . . .. .,, ,,, ,, ,, : : : . .. . . .

HOE 74/~ 036
~063~3~ - -
The starting products were diol of corresponding chain
length having terminal alcohol functions. Since only one ~;~
bromine atom per diol molecule was to be introduced, a
method had to be chosen wherein the reaction product was
immediately eliminated from the proper reaction medium and ~; ;
thus further reaction was excluded. For this purpose the
extraction method was suitable.
In a round flask the diol and hydrobromic acid were placed.
The starting products were overlaid with petroleum benzine
or with benzene/petroleum benzine. The selection of the
extraction agent depended on the insolubility of the diol
and on the good solubility of the reaction products therein.
The round flask was equipped with a reflux condenser. While
energetically stirring by means o a magnetically operated
stirrer, the mixture was then refluxed by means of an adequate
heating device until the starting product had completely
reacted. The proceeding reaction was checked by means of ~-
thin-layer chromatograms.
Subsequently the extraction medium phase was separated and
dried with calcium sulfate. After the siccative had been
filtered off the extraction medium was eliminated in the
rotary evaporator. The residue was subjected to a
fractionated distillation in an oil pump vacuum.
:
- 13 -
-- , : . . .
.. , . . . .: :.
:: : -: : ~,, : :. ;.:: :: . ., :;

1~63131 HOE 74/B 036
The yields were about 80 to 95% o~ the theoretical yield,
calculated on the diol used.
4-~romobutanol-(1) and 5-bromopentanol-(1) were prepared
as follows: ~;
0,25 mol = 22,5 g of 1,4-butanediol or 26 g o~ 1,5-pentane-
diol,
0,48 mol = 80 g of HBr(47~,
500 ml of benzene and
50 ml of petroleumbenzine, boiling point 100 to 140C,
were refluxed for 6,5 and 6 hours, respectively.
The rest of the brominated alcohols was prepared as ~ollows~
0,25 mol = 29,6 g of 1,6-hexanediol or the corresponding diol,
0,48 mol = 80 g of HBr(47%),
1500 ml of petroleum benzine, boiling point 100 to 140C,
were refluxed.
Reaction product Reaction time physical constants
4-bromobutanol-(1) 6,5 hr b.p.(0.7 mm Hg) 58 to 60C5-bromopentanol-~1) 6 hr b.p.(0.5 mm Hg) 72 to 74C6-bromohexanol-tl) 1,5 hr b.p.(0.6 mm Hg) 85 to 87C7-bromoheptanol-~1) 1,5 hr b.p.(0.5 mm Hg) 87 to 89C8-bromooctanol-(1) 1 hr b.p.~0.5 mm Hg) 110 to 112C
9-bromononanol-(1) 1 hr b.p.(0.4 mm Hg) 112 to 114C
10-bromodecanol-(1) 30 min b.p.(0.3 mm Hg) 124 to 126C ~-
- 14 -
.
-. ,, ., .:, ,. ; .:.- : , , .. : .: . :. . . ,:: .. ,
:. : ... . :: . .: . :-: :. :i .. : :.
- : :~ : : . .:
-

~3~3~ HOE 74/B 036
Including 8-bromooctanol-(1) the reaction products were -
colourless liquids. 9-Bromononanol(l) and 10-bromodecanol~
are white and solid products at room temperature. Brominated
alcohols of greater chain length may principally be prepared
according to the same process. Since these reaction products
are all solid products, they are purified by recrystallization.
(b) Preparation of ~ -bromoalkylphosporic acid dichloride:
32 mmol = 30 ml of phosphorus oxytrichloride (freshly
distilled, boiling point 105 to 107C) in
70 ml of absolute chloroform tdistilled for 90 minutes with
circulation over P205)
were placed in a round flask. At room temperature, nitrogen i
was introduced into the solution for a short time to expel air.
The flask was equipped with a dropping funnel and sealed air-
tight. While stirring by means of a magnetically operated
stirrer, 20 mmol of the brominated alcohol of desired chain
length in 50 ml of absolute chloroform were added dropwise
slowly at room temperature with the exclusion of moisture.
Stirring was continued for about 12 hours. The hydrogen
chloride resulting from the reaction as well as excess
phosphorus oxytrichloride and chloroform were eliminated
at 30C in the rotary evaporator. To eliminate every trace of
phosphorus oxytrichloride toluene was added and likewise
drained off.
- 15 -
: , : . :: - ~ - ~ :. . :
~:
: : .. ,
,

1063~31 HOE 74/B 036
The yield was 95 to 100~ and the conversion reaction can
be checked by thin-layer chromatography.
Example 3
General preparation of alkylesters of phospholipid acid
and of structural analogues thereof:
The phosporylation agent prepared in Example 1 or 2 (0.3
mol~ was dissolved in 100 ml of absolute chloroform (distilled
for 90 minutes with circulation over P2O5), and the solution
was cooled to 0 to 5C in an ice bath. While stirring by
means o a magnetically operated stirrer, 60 g (0.6 mol) of
absolute triethylamine tdried over lithiumaluminumhydrlde
and freshly distilled) were added dropwise to 50 ml of absolute
chloroform. The ice bath was then replaced by a water bath
of 20C. While steadily stirring, a solution of the corresponding
starting substance (0,15 mol) in 150 ml of absolute chloro-
form was added dropwise to the phosporylation mixture.
Checking by means of thin-layer chromatography made sure
that the reaction was almost complete already after the drop-
wise addition. After another 6 hours at 40C the reaction
mixture was freed in the rotary evaporator at 35C from
solvent, and the residue was taken up in 450 ml of tetrahydro-
furan. While stirring, 1 M sodium acetate solution of pH 8.4 ~ -
- 16 -
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~0~3~3~ HOE 74/B 036
was added to the suspension or solution of the reaction ;
mixture in tetrahydrofuran until the water phase remained
neutral (pH about 7). For this purpose, about 450 ml of
lM sodium acetate solution had to be added. The hydrolysed
reaction product was extracted as the sodium salt by means
of 450 ml of diisopropylether. The water phase was again
extracted by means of 200 ml of diisopropylether. The combined
diisopropylether extracts were mixed while stirring with
10 g of sodium carbonate to eliminate water and to assure a `
complete conversion of the reaction product into the sodium
salt.
For the preparation of derivatives having less than a total
o 14 carbon atoms, the reaction solution was acidified with
HCl (pH about 2) prior to the extraction with diisopropyl
ether. Derivatives having a very short chain were better
extxacted as the free acids and can be crystallized by care-
fully adding sodium methylate in methanol.
The diisopropylether phase was filtered and the filtrate was
evaporated in vacuo. The residue was recrystallized from
ethylmethylketone/acetone mixtures~ Generally the resulting
reaction products are analytically pure. Otherwise a complete
purification of the products is brought about by chromato-
graphy on silica gel. The yields of analytically pure product ~ -~
vary between 70 and 90% (calculated on the starting products
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1063~31 HOE 74/B 036
used).
The following compounds were prepared:
Compound of Group 1:
sn-1,2-dimyristoylglycerol-3-phosphoric acid methyl ester, as
' 32 62 8 (628.8)
calculated: C 61.12% H9.94~ P 4.93%.
The data found complied with the calculated values.
Compound of Group 2:
sn-l-myristoylglycerol-3~phosphoric acid methyl ester, as sodium
salt, C18H36NaO7P (418.5)
calculated: C 51.67~ H 8.67% P 7.40%.
The data found complied with the calculated values.
Compound of Group 3:
1/2,3,4,5-pentapalmitoyl-D-mannitol-6-phosporic acid butyl ester,
as sodium salt, C90Hl72NaOl4P (1532.3)
calculated: C 70.55% H 11.32~ P 2.02%.
The data found complied with the calculated values.
Compound of Group 4:
/ Glyceroldioctyl etherphosphoric acid-(3)-~-bromoethyl ester,
as sodium salt, C21H43BrNaO6P t525.5)
calculated: C 48.00% H 8.25% Br 15,21% P 5.90%.
The data found complied with the calculated values.
Compound cf Group 5:
Diheptadecyl ketone glycerol-3-phosphoric acid octyl ester,
as sodium salt, C46H92NaO6P (795.21)
calculated: C 69.48% H 11.66% P 3.90%.
The data found complied with the calculated values.
Compound of Group 6:
Cyclopentadecyle ketone glycerol-3-phophoric acid-B-bromoethylester,
- 18 -
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HOE 74/B 036
1~63~31
as sodium salt, C20H37BrNap (484-4)
calculated: C 49,59~ H 7,70% Br 16,49~ P 6,39%.
The data found complied with the calculated values.
Compound of Group 7:
Oleoylhexanediol-(1,6)-phosphoric acid isopropyl ester, as
sodium salt, C27H52NaO6P (526.68)
calculated: C 61.57% H 9.52% P 5.88%.
The data found complied with the calculated values.
Compound of Group 8:
Propanediol-(1,3)-hexadecyl ether phosphoric acid hexyl ester,
as sodium salt, C25H52NaO5P (486.7)
calculated: C 61,70% EI 10,77% P 6,37%.
The data Eound complied with the calculated values.
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.