Antihypertensive phosphate derivatives

Antihypertensive phosphate derivatives having the following formula are described: ##STR1## wherein X is selected from the group consisting of a phenyl radical substituted at any position with a C.sub.1 -C.sub.20 branched or straight chain alkoxy or benzyloxy and optionally substituted by any other positions with one or more groups consisting of C.sub.1 -C.sub.15 branched or straight chain alkyl, C.sub.1 -C.sub.15 branched or straight chain alkoxy and halogen, and a naphthalene radical substituted at any position with a C.sub.1 -C.sub.20 branched or straight chain alkoxy or benzyloxy and optionally substituted at any other positions with one or more groups consisting of C.sub.1 -C.sub.15 branched or straight chain alkyl, C.sub.1 -C.sub.15 branched or straight chain alkoxy and halogen; T is selected from the group consisting of hydrogen and ##STR2## wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 branched or straight chain alkyl, C.sub.1 -C.sub.4 branched or straight chain alkoxy and C.sub.1 -C.sub.4 branched or straight chain alkylamino; Y is selected from the group of bivalent radicals consisting of --(CH.sub.2).sub.p -- and --(CHR).sub.p --, wherein p is an integer from 2 to 10 and the moiety --(CHR).sub.p -- represents an alkylene chain substituted with one or more C.sub.1 -C.sub.8 alkyl groups or phenyl groups; Z is selected from the group consisting of --N.sup.+ (R.sub.2).sub.3 and ##STR3## wherein q is an integer from 4-7 and R.sub.2 may be the same or different and is selected from the group consisting of hydrogen and C.sub.1 -C.sub.4 branched or straight chain alkyl.

BACKGROUND OF INVENTION 
This invention pertains to novel phosphate derivatives, and to methods of 
preparation of such compounds. This invention is also concerned with 
compositions useful in the treatment of hypertension. 
It is estimated that approximately fifteen percent (15%) or more of the 
adult population in the United States is hypertensive, i.e., having blood 
pressures greater than or equal to about 160/95 mm Hg. Of that population, 
approximately one-half is unaware of their hypertensive condition. An 
untreated hypertensive is at great risk of developing disabling or fatal 
left ventricular failure, myocardial infarction, cerebral hemorrhage or 
infarction, and renal failure at an early age. Hypertension is generally 
considered the most important risk factor predisposing to coronary and 
cerebral atherosclerosis. However, it is believed that effective medical 
control of hypertension will prevent or forestall all complications 
associated with hypertension, and will prolong the life of the 
hypertensive patient. 
Drug therapy of hypertension includes use of diuretics, sympathetic 
depressants (e.g., -blockers such as reserpine), vasodilators and finally 
blockers of sympathetic transmission at the neuroeffector junction (e.g., 
guanethidine or clonidine). 
Among the vasodilators currently employed in hypertension therapy are 
diazoxide and sodium nitroprusside. Side effects of diazoxide therapy 
include nausea, vomiting, hyperglycemia and tachycardia. Side effects from 
sodium nitroprusside therapy include nausea, vomiting, agitation, muscular 
twitching and cutis anserina if blood pressure is reduced too rapidly. 
Minoxidil is also often used as a vasodilator in hypertension therapy. 
However, the side effects of minoxidil include sodium and water retention, 
and hirsutism. Hydralazine, a mild vasodilator, is also employed. Its side 
effects include headaches, tachycardia, fluid retention, aggravation of 
angina, gastrointestinal irritation, lupus-like syndrome, drug fever and 
psychosis. 
Acetyl glyceryl ether phosphocholines have been recognized as having potent 
biological activity in platelet activation, and in vasoconstriction and 
vasodilation. See, e.g., U.S. Pat. No. 4,329,302, which issued on May 11, 
1982 to Hanahan, et al. Such phosphocholines have been identified as both 
a platelet activation factor (PAF) and an antihypertensive polar 
renomedullary lipid (APRL). See R. L. Wykle, et al., FEBS LETTERS, 141: 
29-32 (1982); M. L. Blank, et al., BIOCHEMICAL AND BIOPHYSICAL RESEARCH 
COMMUNICATIONS, 90: 1194-1200 (1979). Antihypertensive phosphocholines do 
not occur as pre-formed components in the body; rather, such 
phosphocholines are synthesized by certain cells. See J. Benveniste, et 
al., INT. ARCHS. ALLERGY APPL. IMMUNN., 66 (Supp. 1): 121-126 (1981); E. 
E. Muirhead, HYPERTENSION, 2: 444-464 (1980). APRL has been described as 
being accountable in great measure for the endocrine-type antihypertensive 
action exerted by the renal medullary and the renomedullary interstitial 
cells. M. L. Blank, et al., ID. 
BRIEF SUMMARY OF THE INVENTION 
The phosphate derivatives of this invention are selected from those of the 
formula 1: 
##STR4## 
wherein X is selected from the group consisting of a phenyl radical 
substituted at any position with a C.sub.1 -C.sub.20 branched or straight 
chain alkoxy or benzyloxy and optionally substituted at any other 
positions with one or more groups consisting of C.sub.1 -C.sub.15 branched 
or straight chain alkyl, C.sub.1 -C.sub.15 branched or straight chain 
alkoxy and halogen, and a naphthalene radical substituted at any position 
with a C.sub.1 -C.sub.20 branched or straight chain alkoxy or benzyloxy 
and optionally substituted at any other positions with one or more groups 
consisting of C.sub.1 -C.sub.15 branched or straight chain alkyl, C.sub.1 
-C.sub.15 branched or straight chain alkoxy and halogen; T is selected 
from the group consisting of hydrogen and 
##STR5## 
wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 
-C.sub.4 branched or straight chain alkyl, C.sub.1 -C.sub.4 branched or 
straight chain alkoxy and C.sub.1 -C.sub.4 branched or straight chain 
alkylamino; Y is selected from the group of bivalent radicals consisting 
of --(CH.sub.2).sub.p -- and --(CHR).sub.p --, wherein p is an integer 
from 2 to 10 and the moiety --(CHR).sub.p -- represents an alkylene chain 
substituted with one or more C.sub.1 -C.sub.8 alkyl groups or phenyl 
groups; Z is selected from the group consisting of --N.sup.+ 
(R.sub.2).sub.3 and 
##STR6## 
wherein q is an integer from 4-7 and R.sub.2 may be the same or different 
and is selected from the group consisting of hydrogen and C.sub.1 -C.sub.4 
branced or straight chain alkyl. 
The compounds of this invention can be prepared as racemic mixtures or as 
the individual R and S enantiomers. Such compounds have antihypertensive 
activity. 
DETAILED DESCRIPTION OF THE INVENTION 
In order to prepare the products of this invention, represented by the 
above formula 1, certain intermediate phenol and naphthalenol derivatives 
must be prepared as described hereinbelow in Flowsheet A, wherein the 
formula HO--X'--OH represents a dihydroxy benzene or naphthalene 
optionally substituted at any positions with one or more groups consisting 
of C.sub.1 -C.sub.15 branched or straight chain alkyl, C.sub.1 -C.sub.15 
branched or straight chain alkoxy and halogen and wherein R.sub.3 is a 
C.sub.1 -C.sub.20 branched or straight chain alkyl group or benzyl group 
and J is a halogen atom (I, Br or Cl). According to Flowsheet A a 
dihydroxy compound 2 is alkylated with one equivalent of an alkyl halide 3 
using sodium hydride in an inert solvent such as dimethylformamide to give 
the desired monoalkylated compound 4 and the dialkylated compound 5. In 
those cases where 2 is a symmetrical compound the resulting reaction 
mixture is composed of unreacted 2, monoalkylated compound 4 and 
dialkylated compound 5. The desired monalkylated compound 4 can be 
separated from the mixture by a combination of short path distillation and 
recrystallization and, if necessary, chromatography. In those cases where 
compound 2 is not symmetrical, two monoalkylated regio isomers are 
obtained in addition to the dialkylated compounds. The monoalkylated 
compounds can be isolated by a combination of short path distillation and 
recrystallization. The resulting regio isomers can then be separated by 
various chromatographic techniques well known in the art. 
##STR7## 
The compounds of this invention represented by structure 20 are prepared as 
outlined hereinbelow in Flowsheet B, wherein X', T, Y, Z, R.sub.3, 
R.sub.1, p, q, and R.sub.2 are as defined above. The reaction of solketal 
6 will mesyl chloride using an amine base such as triethylamine in an 
inert solvent such as methylene chloride or diethyl ether gives the 
mesylate 7. Treatment of the phenol or naphthalenol 4 with sodium hydride 
in an inert solvent such as dimethylformamide forms the sodium salt which 
reacts with mesylate 7 (if necessary sodium iodide is added to accelerate 
the reaction) to give the compound 8. The diol protecting of 8 can be 
removed using p-toluenesulfonic acid or an acidic ion exchange resin in 
methanol to give the diol 9. The diol 9 is reacted with a reagent which 
only functionalizes the primary hydroxyl group; one such reagent is 
p-anisylchlorodiphenylmethane 10 in pyridine or mixed solvent containing 
pyridine; this provides the monoprotected compound 11. This is converted 
to the compound 12 by alkylation with benzyl bromide using sodium hydride 
in an inert solvent. Treatment of 12 with methanol and an acidic catalyst 
such as p-toluenesulfonic acid or an acidic ion exchange resin gives the 
alcohol 13. The reaction of 13 with the phosphorous reagents 14a or 14b in 
an inert solvent such as carbon tetrachloride with a base such as 
triethylamine gives, after hydrolysis in a buffer such as aqueous sodium 
acetate, the phosphate compound 15. The reaction of 15 with amines 16a or 
16b in a refluxing inert solvent or in a bomb at elevated temperatures 
affords compound 17. The benzyl protecting group of 17 is removed by 
hydrogenolysis to give the alcohol 18. Representative alkyl amines capable 
of being used in the present process are shown in Table III following 
Example 54 herein. 
The compounds represented by the formula 18 can be converted to compounds 
20 of this invention wherein R.sub.1 is an alkyl group by the reaction of 
18 with an anhydride 19a in the presence of a base catalyst such as 
triethylamine in an inert solvent such as chloroform. 
The compounds represented by the formula 18 can be converted to compounds 
20 of this invention wherein R.sub.1 is a C.sub.1 -C.sub.4 alkoxy group by 
the reaction of 18 with a pyrocarbonate 19c in the absence of solvent at 
elevated temperature (about 50.degree.-150.degree. C.). 
The compounds represented by the formula 18 can be converted to compounds 
20 of this invention wherein R.sub.1 is hydrogen by the reaction of 18 
with about 97% formic acid at room temperature for about 3 to 7 days. 
The compounds represented by the formula 18 can be converted to compounds 
20 of this invention wherein R.sub.1 is a C.sub.1 -C.sub.4 alkylamino 
group by treatment of 18 with an isocyanate 19b in an inert solvent such 
as toluene at about 25.degree.-100.degree. C. for about 1-7 days. 
Since compound 6 is available in either the optically active R or S forms, 
or in the optionally inactive racemic form, the compounds of this 
invention represented by the formula 20 can be prepared in the 
corresponding optically active R and S configurations or in the optically 
inactive racemic form by choosing the proper starting material [E. Baer, 
BIOCHEMICAL PREP., 2: 31 (1952); M. E. Jung and T. J. Shaw, J. AMER. CHEM. 
SOC., 102: 6304 (1980)]. 
##STR8## 
In those cases where R.sub.3 is a benzyl group, a modified method is used 
to prepare the compounds of this invention as shown below in Flowsheet C. 
The reaction of 11 with an anhydride 19a using an amine base such as 
triethylamine in an inert solvent gives the compound 21. Removal of the 
p-methoxytrityl group of 21 without migration of the acyl moiety is 
accomplished by the boric acidsilic acid chromatographic technique of D. 
Buchnea, LIPIDS, 9, 55 (1974). The phosphate group is then introduced as 
described above. Finally, reaction with amines 16a and 16b gives the 
compounds of this invention represented by formula 24. 
##STR9## 
The methods for the preparation of the phosphorous reagents 14a and 14b 
used to prepare the compounds of this invention are described in detail in 
a copending application for U.S. Ser. No. 457,097, filed Jan. 10, 1983, 
which issued as U.S. Pat. No. 4,640,913 on Feb. 3, 1987, which is 
incorporated herein by reference, and in the following references: E. Baer 
and N. Z. Stanacey, J. BIOL. CHEM., 240, 3754 (1965); A. Eberhard and F. 
H. Westheimer, J. AMER. CHEM. SOC., 37, 253 (1965). By using such 
procedures the bromo alcohols of Table I are converted to the indicated 
phosphorodichlorodates. 
TABLE I 
______________________________________ 
Bromo Alcohol Phosphorodichlorodate 
______________________________________ 
1-bromoethanol 2-bromoethyl phosphorodichloro- 
date 
3-bromopropanol 
3-bromopropyl phosphorodi- 
chlorodate 
2-bromopropanol 
2-bromopropyl phosphorodi- 
chlorodate 
2-bromo-1-methylethanol 
2-bromo-1-methylethyl phos- 
phorodichlorodate 
4-bromobutanol 4-bromobutyl phosphorodichloro- 
date 
5-bromopentanol 
5-bromopentyl phosphorodichlorodate 
3-bromo-3-methylpropanol 
3-bromo-3-methylpropyl phos- 
phorodichlorodate 
3-bromo-2-methylpropanol 
3-bromo-2-methylpropyl phos- 
phorodichlorodate 
3-bromo-1-methylpropanol 
3-bromo-1-methylpropyl phos- 
phorodichlorodate 
2-bromo-2-phenylethanol 
2-bromo-2-phenylethyl phos- 
phorodichlorodate 
3-bromo-2-phenylpropanol 
3-bromo-2-phenylpropyl phos- 
phorodichlorodate 
______________________________________ 
The compounds of the present invention are active as hypotensive agents as 
evidenced by their activity in the following test, the results of which 
are shown in Table II. 
Under ether anesthesia, Weeks type cannulas (Peterson Technics) were 
surgically implanted in the abdominal aorta and vena cava of spontaneously 
hypertensive rats (Taconic Farms, Germantown, NY) and passed 
subcutaneously to the back of the neck where they were exteriorized. The 
cannulas were filled with saline, plugged and the rats returned to single 
cages where they were allowed food and water ad libitum. 
At least three days following implantation of the cannulas, the rats were 
weighed and placed in Broome style restraining cages. The plug was removed 
from the aortic catheter which was connected to an arterial pressure 
transducer (Statham P23ID) using PE 100 polyethylene tubing and a stepdown 
connector fabricated from stainless steel hypodermic tubing. Mean arterial 
blood pressure was obtained by electrical damping of the pulse pressure 
channel. Heart rate was obtained from a tachograph triggered by the pulse 
pressure channel. All parameters were monitored on a Grass physiological 
recorder (Model 7). 
The plug was removed from the vena cava catheter and a PE 20 polyethylene 
tubing extension was added using a piece of stainless steel hypodermic 
tubing. The other end was terminated with a 27G needle and one ml syringe. 
All drugs were dissolved in saline or a mixture of ethanol and saline 
(25:75 V:V) such that the volume injected intravenously was about 0.1 
ml/100 g body weight. All drugs were flushed in with about 0.2 ml saline. 
Blood pressure was continually monitored both before and after 
introduction of the test compound. 
TABLE II 
______________________________________ 
Peak .DELTA. Mean 
No. Arterial Blood 
Dose of Pressure 
Compound (.mu.g/kg) 
Rats (mmHg) 
______________________________________ 
7-[[[5-(dodecyloxy)-1- 
10 4 -19.6 
naphthalenyl]oxy]methyl]- 
30 4 -45.9 
4-hydroxy-N,N,N--trimethyl- 
100 4 -79.8 
9-oxo-3,5,8-trioxa-4-phos- 
300 4 -95.9 
phadecan-1-aminium, 
4-oxide, hydroxide, inner 
salt 
7-[[[7-(dodecyloxy)-2- 
1 3 -11.0 
naphthalenyl]oxy]methyl]- 
3 3 -44.3 
4-hydroxy-N,N,N--trimethyl- 
10 3 -74.3 
9-oxo-3,5,8-trioxa-4-phos- 
phadecan-1-aminium, 
4-oxide, hydroxide, inner 
salt 
7-[[[4-(dodecyloxy)-1- 
10 4 -6.8 
naphthalenyl]oxy]methyl]- 
30 4 -16.1 
4-hydroxy-N,N,N--trimethyl- 
100 4 -30.5 
9-oxo-3,5,8-trioxa-4-phos- 
300 4 -46.0 
phadecan-1-aminium, 
4-oxide, hydroxide, inner 
salt 
7-[[[6-(dodecyloxy)-2- 
10 5 -13.9 
naphthalenyl]oxy]methyl]- 
30 5 -26.7 
4-hydroxy-N,N,N--trimethyl- 
300 5 -61.4 
9-oxo-3,5,8-trioxa-4-phos- 
1000 5 -89.3 
phadecan-1-aminium, 
4-oxide, hydroxide, inner 
salt 
7-[[3-(dodecyloxy)-2-meth- 
0.1 4 -8.1 
ylphenoxy]methyl]-4- 
0.3 4 -47.7 
hydroxy-N,N,N--trimethyl-9- 
1.0 4 -79.9 
oxo-3,5,8-trioxa-4-phos- 
3.0 4 -110.4 
phadecan-1-aminium, 
4-oxide, hydroxide, inner 
salt 
7-[[4-(phenylmethoxy)phen- 
10 4 -12.9 
oxy]methyl]-4-hydroxy- 
30 4 - 23.6 
N,N,N--trimethyl-9-oxo- 
100 4 -37.8 
3,5,8-trioxa-4-phosphadec- 
300 4 -70.4 
an-1-aminium, 4-oxide, 
1000 4 -89.7 
hydroxide, inner salt 
______________________________________ 
When the compounds are employed for the above utility, they may be combined 
with one or more pharmaceutically acceptable carries, e.g., solvents, 
diluents and the like, and may be administered orally in such forms as 
tablets, capsules, dispersible powders, granules, or suspensions 
containing, for example, from about 0.05 to 5% of suspending agent, syrups 
containing, for example, from about 10 to 50% of sugar, and elixirs 
containing, for example, from about 20 to 50% ethanol, and the like, or 
parenterally in the form of sterile injectable solutions or suspensions 
containing from about 0.05 to 5% suspending agent in an isotonic medium. 
Such pharmaceutical preparations may contain, for example, from about 
0.05% up to about 90% of the active ingredient in combination with the 
carrier, more usually between about 5% and 60% by weight. 
The effective dosage of active ingredient employed may vary depending on 
the particular compound employed, the mode of administration and the 
severity of the condition being treated. However, in general, satisfactory 
results are obtained when the compounds of the invention are administered 
at a daily dosage of from about 0.005 mg to about 100 mg/kg of animal body 
weight, preferably given in divided doses two to four times a day, or in 
sustained release form. For most large mammals the total daily dosage is 
from about 500 .mu.g to about 5,000 mg preferably from about 350 .mu.g to 
3,500 mg. Dosage forms suitable for internal use comprise from about 25 
.mu.g to 500 mg of the active compound in intimate admixture with a solid 
or liquid pharmaceutically acceptable carrier. This dosage regimen may be 
adjusted to provide the optimal therapeutic response. For example, several 
divided doses may be administered daily or the dose may be proportionally 
reduced as indicated by the exigencies of the therapeutic situation. A 
decided practical advantage is that these active compounds may be 
administered orally as well as by intravenous, intramuscular, or 
subcutaneous routes. Solid carriers include starch, lactose, dicalcium 
phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid 
carriers include sterile water, polyethylene glycols, non-ionic 
surfactants and edible oils such as corn, peanut and sesame oils, as are 
appropriate to the nature of the active ingredient and the particular form 
of administration desired. Adjuvants customarily employed in the 
preparation of pharmaceutical compositions may be advantageously included, 
such as flavoring agents, coloring agents, preserving agents, and 
antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA. 
The preferred pharmaceutical compositions from the stand-point of ease of 
preparation and administration are solid compositions, particularly 
tablets and hard-filled or liquid-filled capsules. Oral administration of 
the compounds is preferred. 
These active compounds may also be administered parenterally or 
intraperitoneally. Solutions or suspensions of these active compounds as a 
free base or pharmacologically acceptable salt can be prepared in water 
suitably mixed with a surfactant such as hydroxypropylcellulose. 
Dispersions can also be prepared in glycerol, liquid polyethylene glycols, 
and mixtures thereof in oils. Under ordinary conditions of storage and 
use, these preparations should contain a preservative to prevent the 
growth of microorganisms. 
The pharmaceutical forms suitable for injection use include sterile aqueous 
solutions or dispersions and sterile powders for the extemporaneous 
preparation of sterile injectable solutions or dispersions. In all cases, 
the form must be sterile and must be fluid to the extent that easy 
syringability exists. It must be stable under the conditions of 
manufacture and storage and must be preserved against the contaminating 
action of microorganisms such as bacteria and fungi. The carrier can be a 
solvent or dispersion medium containing, for example, water, ethanol, 
polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), 
suitable mixtures thereof, and vegetable oils. 
In addition to the above utilities, some of the compounds of this invention 
(such as 15 of flowsheet A and 32 of flowsheet B) are useful for the 
preparation of other compounds of this invention. 
In particular, it has been found that 
7-[[3-(dodecyloxy)-4,6-(di-t-butyl)phenoxy]methyl]-4-hydroxy-N,N,N-trimeth 
yl-9-oxo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner 
salt can decrease mean arterial blood pressure 50 mm Hg in spontaneously 
hypertensive rats at a dose of about 13.0 .mu.g/Kg, but without platelet 
aggregation at such dose. 
The invention will be more fully described in conjunction with the 
following specific examples which are not to be construed as limiting the 
scope of the invention. In addition, other applicable procedures are 
described in the aforementioned copending application, Ser. No. 457,097, 
filed Jan. 10, 1983 which issued as U.S. Pat. No. 4,640,913 on Feb. 3, 
1987;

EXAMPLE 1 
5-(Dodecyloxy)-1-naphthalenol 
To a suspension of 9.14 g of washed (hexane) 50% soldium hydride in 100 ml 
of dimethylformamide containing 2.28 g of sodium iodide, under argon, was 
added with stirring a solution of 24.4 g of 1,5-dihydroxynaphthalene in a 
mixture of 200 ml of dimethylformamide and 100 ml of tetrahydrofuran over 
30 minutes. After stirring for an additional 30 minutes, 37.97 g of 
n-dodecyl bromide was added. This mixture was stirred 2 hours, then poured 
into water and extracted with ether. The ether layer was separated, dried 
over magnesium sulfate and activated charcoal and filtered through silica 
gel. The solvent was removed and the residue extracted four times with 800 
ml of boiling hexane. The hexane solutions were filtered while hot, the 
solvent removed and the residue recrystallized from hexane, giving 13 g of 
the desired compound as a grey powder, mp 79.degree.-83.degree. C. 
EXAMPLE 2 
3-(Dodecyloxy)-2-methylphenol 
To a stirred suspension of 36.23 g of washed (hexane) 50% sodium hydride in 
300 ml of dimethylformamide, under argon, was added over 1.5 hours a 
solution of 75 g of 2-methylresorcinol in a mixture of 200 ml of 
dimethylformamide and 100 ml of tetrahydrofuran. This solution was cooled 
in an ice bath and 9.06 g of sodium iodide was added followed by the 
addition of 150.58 g of n-dodecyl bromide over one hour. This mixture was 
stirred at room temperature for 2.5 hours, then quenched with dilute 
hydrochloric acid and extracted with ether. The ether extract was dried, 
filtered through silica gel and the solvent removed. The residue was 
distilled via a Kugelrohr at 0.1 mm. The fraction distilled at 
170.degree.-200.degree. C. was redistilled at 170.degree. C., 0.1 mm. The 
distillate was passed through a column of silica gel, eluting with 
ether:hexane (1:1). The solvent was removed and the residue redistilled at 
170.degree. C., 0.1 mm giving 53.5 g of the desired compound as an oil 
which crystallized, mp 38.degree.-39.degree. C. 
EXAMPLE 3 
7-(Dodecyloxy)-2-naphthalenol 
To a suspension of 19.47 g of washed (hexane) 50% sodium hydride in 200 ml 
of dimethylformamide, under argon, was added with stirring a solution of 
50 g of 2,7-dihydroxynaphthalene in a mixture of 100 ml of 
dimethylformamide and 200 ml of tetrahydrofuran over one hour. The mixture 
was cooled to 0.degree. C. and 92.47 g of n-dodecyl iodide was added. The 
mixture was heated to 60.degree. C. and then stirred at room temperature 
overnight; diluted with hydrochloric acid and extracted with ether. The 
ether extract was dried over magnesium sulfate and activated charcoal and 
the solvent removed. The residue was fractionated on a Kugelrohr. The 
fraction at 170.degree.-250.degree. C. was collected as a solid and 
recrystallized from hexane, giving 10.4 g of the desired compound as a 
white solid, mp 97.degree.-98.degree. C. 
EXAMPLE 4 
4-(Dodecyloxy)-1-naphthalenol 
To a stirred suspension of 17.25 g of washed (hexane) 50% sodium hydride in 
200 ml of dimethylformamide, under argon, was added a solution of 44.3 g 
of 1,4-dihydroxynaphthalene in a mixture of 200 ml of dimethylformamide 
and 100 ml of tetrahydrofuran over one hour. The mixture was cooled to 
0.degree. C. and then 4.15 g of sodium iodide and 68.93 g of n-dodecyl 
bromide were added. This mixture was stirred at room temperature for 2 
hours, water was added, the mixture was acidified with sulfuric acid and 
then extracted with ether. The ether extract was dried, the solvent 
removed and the residue distilled on a Kugelrohr. The fraction distilling 
at 160.degree.-230.degree. C. (0.1 mm) was collected and redistilled. The 
fraction distilling at 200.degree.-210.degree. C. (0.1 mm) was collected 
and recrystallized from hexanes, giving 27 g of the desired compound, mp 
86.degree.-88.degree. C. 
EXAMPLE 5 
6-(Dodecyloxy)-2-naphthalenol 
To a suspension of 14.98 g of washed (hexane) 50% sodium hydride in 160 ml 
of dimethylformamide, under argon, was added with stirring over one hour, 
a solution of 40 g of 2,6-dihydroxynaphthalene in 150 ml of 
tetrahydrofuran and 80 ml of dimethylformamide. To this solution was added 
3.74 g of sodium iodide and 62.24 g of n-dodecyl bromide. The mixture was 
heated to 50.degree. C., then stirred at room temperature for 4 hours, 
water was added and the mixture extracted with ether and ethyl acetate. 
The organic extract was dried, the solvent removed and the residue mixed 
with hot carbon tetrachloride and filtered. The solvent was removed from 
the filtrate and the residue was purified by HPLC, eluting with 
chloroform:hexane (2:3). The solid was recrystallized from hexane, giving 
3.5 g of the desired compound, mp 85.degree.-87.degree. C. 
EXAMPLE 6 
2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenol 
To a suspension of 21.04 g of washed (hexane) 50% sodium hydride in 200 ml 
of dimethylformamide, under argon, was added with stirring 5.06 g of 
sodium iodide followed by the dropwise addition of a solution of 
4,6-ditertiary-butylresorcinol in 200 ml of dimethylformamide and 150 ml 
of tetrahydrofuran over one hour. Then, 84.08 g of n-dodecyl bromide was 
added dropwise over 1/2 hour and this mixture was stirred overnight. The 
mixture was poured into water and extracted with ether. The ether extract 
was washed with water, dried and the solvent removed. The residue was 
distilled on a Kugelrohr collecting the distillate from 
180.degree.-210.degree. C. (0.5 mm). This was redistilled, collecting the 
fraction 180.degree.-205.degree. C. (0.5 mm), which gave 38 g of the 
desired product as an orange oil. 
EXAMPLE 7 
3-[[5-(Dodecyloxy)-1-naphthalenyl]oxy]-1,2-propanediol 
To a suspension of 2.19 g of 50% sodium hydride in 80 ml of 
dimethylformamide, under argon, was added with stirring a solution of 12 g 
of 5-(dodecyloxy)-1-naphthalenol in 60 ml of tetrahydrofuran over 1/2 
hour. A 2 g portion of sodium iodide and 9.77 g of solketal mesylate were 
added and the mixture was stirred overnight. The mixture was diluted with 
water and extracted with ether. The ether extract was washed with dilute 
sodium hydroxide, then brine, dried, filtered through silica gel and the 
solvent removed. The residue was refluxed in a mixture of 100 ml of 
methanol, 16 ml of water and 1 ml of concentrated sulfuric acid for one 
hour, then cooled and the solid collected. This solid was dissolved in 
boiling chloroform containing magnesium sulfate and activated carbon and 
filtered through diatomaceous earth. The filtrate was evaporated and the 
residue recyrstallized from carbon tetrachloride, giving 8 g of the 
desired compound as an off-white solid, mp 143.degree.-144.degree. C. 
EXAMPLE 8 
3-[3-(Dodecyloxy)-2-methylphenoxy]-1,2-propanediol 
To a stirred suspension of 5.74 g of washed (hexane) 50% sodium hydride in 
175 ml of dimethylformamide, under argon, was added 28 g of 
3-(dodecyloxy)-2-methylphenol in 120 ml of tetrahydrofuran over one hour. 
A 4 g portion of sodium iodide and 23.29 g of solketal mesylate were 
added, the mixture was stirred at 80.degree. C. overnight, then cooled and 
water was added. This mixture was extracted with ether. The ether extract 
was washed with dilute sodium hydroxide, then brine, dried, filtered 
through silica gel and the solvent removed. The residue was refluxed in a 
mixture of 200 ml of methanol, 32 ml of water and 2 ml of concentrated 
sulfuric acid for one hour, then cooled and the solid collected and 
recrystallized from methanol, giving 24.4 g of the desired compound, mp 
76.degree.-78.degree. C. 
EXAMPLE 9 
3-[[7-(Dodecyloxy)-2-naphthalenyl]oxy]-1,2-propanediol 
To a stirred suspension of 1.83 g of washed (hexane) 50% sodium hydride in 
80 ml of dimethyformamide, under argon, was added 10 g of 
7-(dodecyloxy)-2-naphthalenol, 0.46 g of sodium iodide and 40 ml of 
tetrahydrofuran. After 15 minutes 7.14 g of solketal mesylate was added. 
This mixture was stirred at 90.degree. C. overnight, then diluted with 
water and extracted with ether. The ether extract was dried and 
evaporated. The residue was refluxed for one hour in a mixture of 100 ml 
of methanol, 16 ml of water and 1 ml of concentrated sulfuric acid, then 
evaporated. The residue was dissolved in chloroform, washed with water, 
dried and the solvent removed. The residue was recrystallized from 
methanol giving the desired compound as an off-white solid, mp 
92.degree.-94.degree. C. 
EXAMPLE 10 
3-[[4-(Dodecyloxy)-1-naphthalenyl]oxy]-1,2-propanediol 
To a stirred suspension of 3.65 g of washed (hexane) 50% sodium hydride in 
60 ml of dimethylformamide, under argon, was added a solution of 20 g of 
4-(dodecyloxy)-1-naphthalenol in 80 ml of tetrahydrofuran over 1/2 hour 
followed by 0.91 g of sodium iodide and 14.81 g of solketal mesylate. The 
mixture was heated at 80.degree. C. for 8 hours, then stirred at room 
temperature overnight, water was added and the mixture extracted with 
ether. The ether extract was dried, evaporated and the residue refluxed 
for one hour in a mixture of 200 ml of methanol, 32 ml of water and 2 ml 
of concentrated sulfuric acid. The solvent was removed, the residue 
dissolved in chloroform, washed with water, dried and filtered through 
silica gel. The solvent was removed and the residue recrystallized from 
methanol, giving 21 g of the desired compound as a white solid, mp 
102.degree.-104.degree. C. 
EXAMPLE 11 
3-[[6-(Dodecyloxy)- 2-naphthalenyl]oxy]-1,2-propanediol 
To a stirred suspension of 2.1 g of washed (hexane) 50% sodium hydride in 
100 ml of dimethylformamide and 50 ml of tetrahydrofuran, under argon, was 
added 11.5 g of 6-(dodecyloxy)-2-naphthalenol, 0.52 g of sodium iodide and 
8.52 g of solketal mesylate. After stirring one hour the mixture was 
heated at 85.degree. C. overnight, then water was added and the mixture 
was extracted with ether. The ether extract was dried, evaporated and the 
residue refluxed for one hour in a mixture of 100 ml of methanol, 16 ml of 
water and 1 ml of concentrated sulfuric acid. The solvent was removed, the 
residue dissolved in chloroform, washed with water, dried and evaporated. 
This residue was recrystallized from methanol, giving 12.0 g of the 
desired compound as a white solid, mp 133.degree.-134.degree. C. 
EXAMPLE 12 
3-[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-1,2-propanediol 
To a suspension of 3.22 g of washed (hexane) 50% sodium hydride and 0.81 g 
of sodium iodide in 200 ml of dimethylformamide, under argon, was added 
with stirring over one hour a solution of 21 g of 
2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenol in 100 ml of 
tetrahydrofuran followed by 13.08 g of solketal mesylate. The mixture was 
heated at 85.degree. C. overnight, then water was added and the mixture 
was extracted with ether. The ether extract was washed with water, dried 
and the solvent removed. The residue was refluxed for one hour in a 
mixture of 200 ml of methanol, 32 ml of water and 2 ml of concentrated 
sulfuric acid. The methanol was removed, the residue extracted with ether, 
the extract dried and then evaporated. The residue was recrystallized 
twice from methanol-water, giving 20 g of the desired compound as an 
off-white solid, mp 35.degree.-370.degree. C. 
EXAMPLE 13 
1-[[5-(Dodecyloxy)-1-naphthalenyl]oxy]-3-[( 
4-methoxyphenyl)diphenylmethoxy]-2-propanol 
A solution of 7.5 g of 3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-b 
1,2-propanediol in 10 ml of pyridine and 30 ml of tetrahydrofuran was 
warmed on a steam bath until the solid dissolved. A 6.04 g portion of 
p-methoxytrityl chloride was added, the mixture was allowed to stand 
overnight and then the solvent was removed. The residue was mixed with 
ethyl acetate and water. The organic layer was separated, washed with 
brine, dried and the solvent removed. The residue was used in Example 19 
without further purification. 
EXAMPLE 14 
1-[3-(Dodecyloxy)-2-methylphenoxy]-3-[(4-methoxyphenyl)diphenylmethoxy]-2-p 
ropanol 
A mixture of 20 g of 3-[3-(dodecyloxy)-2-methylphenoxy]-1,2-propanediol, 
20.22 g of p-methoxytrityl chloride, 30 ml of pyridine and 90 ml of 
tetrahydrofuran was allowed to stand for 72 hours, then the solvent was 
removed. The residue was mixed with water and extracted with ether. The 
ether extract was washed with water, then brine, dried and the solvent 
removed. The residue was used without further pruification in Example 20. 
EXAMPLE 15 
1-[[7-(Dodecyloxy)-2-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy] 
-2-propanol 
A mixture of 9 g of 3-[[7-(dodecyloxy)-2-naphthalenyl]oxy]-1,2-propanediol, 
8.63 g of p-methoxytrityl chloride, 15 ml of pyridine and 40 ml of 
tetrahydrofuran was allowed to stand overnight. The tetrahydrofuran was 
removed, the remainder poured into water and extracted with ether. The 
ether extract was dried, evaporated and the residue dried in vacuo and 
used without further purification in Example 21. 
EXAMPLE 16 
1-[[4-(Dodecyloxy)-1-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy] 
-2-propanol 
A mixture of 15 g of 3-[[4-(dodecyloxy)-1-naphthalenyl]-1,2-propanediol, 
14.38 g of p-methoxytrityl chloride, 40 ml of pyridine and 100 ml of 
tetrahydrofuran was allowed to stand overnight. The tetrahydrofuran was 
removed, the remainder poured into water and extracted with ether. The 
ether extracted was dried and evaporated giving a green oil which was used 
without further purification in Example 22. 
EXAMPLE 17 
1-[[6-(Dodecyloxy)-2-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy] 
-2-propanol 
A mixture of 10 g of 
3-[[6-(dodecyloxy)-2-naphthalenyl]oxy]-1,2-propanediol, 9.59 g of 
p-methoxytrityl chloride, 30 ml of pyridine and 75 ml of tetrahydrofuran 
was allowed to stand overnight, then the solvent was removed. The residue 
was dissolved in ether, washed with water, then brine, dried and the 
solvent removed. The residue was used without further purification in 
Example 23. 
EXAMPLE 18 
1-[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-3-[(4-methoxyphenyl)di 
phenylmethoxy]-2-propanol 
A mixture of 15 g of 
3-[2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-1,2-propanediol, 
12.46 g of p-methoxytrityl chloride, 40 ml of pyridine and 100 ml of 
tetrahydrofuran was allowed to stand overnight, then the solvent was 
removed. Water was added and the mixture extracted with ether. The ether 
extract was dried, evaporated and the residue dried in vacuo, giving an 
oil which was used without further purification in Example 24. 
EXAMPLE 19 
3-[[5-(Dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol 
To a suspension of 1.34 g of washed (hexane) 50% sodium hydride in 60 ml of 
dimethylformamide containing 4.78 g of benzyl bromide, under argon, was 
added with stirring a solution of 9.96 g of 
1-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy 
]-2-propanol in 30 ml of tetrahydrofuran. After stirring 2 hours, water was 
added and the mixture was extracted with ethyl acetate. The organic 
extract was dried and the solvent removed. The residue was dissolved in a 
mixture of 120 ml of methanol and 60 ml of chloroform, heated to boiling 
and 4 g of strongly acidic ion exchange resin was added. This mixture was 
stirred for one hour, then filtered and the solvent removed. The residue 
was purified by HPLC using hexane:ethyl acetate (4:1) giving 7.5 g of the 
desired compound as a white solid, mp 60.degree.-62.degree. C. 
EXAMPLE 20 
3-[3-(Dodecyloxy)-2-methylphenoxy]-2-(phenylmethoxy)-1-propanol 
To a stirred mixture of 3.93 g of washed (hexane) 50% sodium hydride and 14 
g of benzyl bromide in 90 ml of dimethylformamide, under argon, was added 
34.86 g of 
1-[3-(dodecyloxy)-2-methylphenoxy]-3-[(4-methoxyphenyl)diphenylmethoxy]-2- 
propanol over 45 minutes. After stirring for 2 hours, water was added and 
the mixture was extracted with ether. The ether extract was washed with 
water, dried and the solvent removed. The residue was heated to boiling in 
a mixture of 200 ml of methanol, 50 ml of chloroform and 20 g of a 
strongly acidic ion exchange resin was added. This mixture was stirred for 
two hours, filtered and the solvent removed. The residue was purified by 
HPLC, eluting with hexane:ethyl acetate (4:1), giving 18.47 g of the 
desired compound as a white solid, mp 50.degree.-51.degree. C. 
EXAMPLE 21 
3-[[7-(Dodecyloxy)-2-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol 
To a stirred suspension of 1.6 g of washed (hexane) 50% sodium hydride in 
45 ml of dimethylformamide, under argon, was added a mixture of 5.7 g of 
benzyl bromide and 
1-[[(dodecyloxy)-2-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy]- 
2-propanol in 30 ml of tertrahydrofuran. The mixture was stirred for 2 
hours, then water was added and the mixture was extracted with ether. The 
ether extract was dried, the solvent removed and the residual oil 
dissolved with heat in a mixture of 100 ml of methanol and 50 ml of 
chloroform. A 10 g portion of a strongly acidic ion exchange resin was 
added to the hot solution which was then stirred for one hour, filtered 
and the solvent removed. The residue was purified by HPLC eluting with 
ethyl acetate:hexane (1:4) giving 7.25 g of the desired compound as an oil 
which crystallized on standing, mp 54.degree.-56.degree. C. 
EXAMPLE 22 
3-[[4-(Dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol 
To a stirred suspension of 2.68 g of washed (hexane) 50% sodium hydride and 
9.54 g of benzyl bromide in 80 ml of dimethylformamide, under argon, was 
added a solution of 25.1 g of 
1-[[4-(dodecyloxy)-1-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy 
]-2-propanol in 60 ml of tetrahydrofuran over 15 minutes. The mixture was 
stirred one hour, water was added and this mixture was extracted with 
ether. The ether extract was dried, evaporated and the residue heated to 
reflux in a mixture of 170 ml of methanol and 80 ml of chloroform. A 15 g 
portion of a strongly acidic ion exchange resin was added, this mixture 
was stirred one hour, then filtered and the solvent removed. The residue 
was purified by HPLC eluting with ethyl acetate:hexane (1:4) giving 14.33 
g of the desired compound as an oil which crystallized on standing, mp 
42.degree.-43.degree. C. 
EXAMPLE 23 
3-[[6-(Dodecyloxy)-2-naphthalenyl]oxy] -2-(phenylmethoxy)-1-propanol 
To a stirred suspension of 1.79 g of washed (hexane) 50% sodium hydride in 
55 ml of dimethylformamide, under argon, was added 6.37 g of benzyl 
bromide and a solution of 16.77 g of 
1-[[6-(dodecyloxy)-2-naphthalenyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy 
]-2-propanol in 40 ml of tetrahydrofuran. The mixture was heated to 
55.degree. C., then stirred at room temperature for 3 hours, water was 
added and the mixture was extracted with either. The ether extract was 
evaporated and the residue heated to reflux in a mixture of 150 ml of 
methanol and 60 ml of chloroform. A 13 g portion of a strongly acidic ion 
exchange resin was added and after stirring for one hour the solvent was 
removed. The residue was purified by HPLC eluting with ethyl 
acetate:hexane (1:4) giving 10.64 g of the desired compound as an 
off-white solid, mp 74.degree.-76.degree. C. 
EXAMPLE 24 
3-[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-2-(phenylmethoxy)-1-pr 
opanol 
To a stirred suspension of 2.44 g of washed (hexane) 50% sodium hydride in 
40 ml of dimethylformamide containing 8.7 g of benzyl bromide, under 
argon, was added over 15 minutes a solution of 24.98 g of 
1-[2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-3-[(4-methoxyphenyl)d 
iphenylmethoxy]-2-propanol in 40 ml of dimethylformamide and 60 ml of 
tetrahydrofuran. The mixture was stirred 3 hours, water was added, the 
mixture was extracted with ether and the ether extract evaported. The 
residue was heated to boiling in 170 ml of methanol and 80 ml of 
chloroform, 15 g of a strongly acidic ion exchange resin was added and the 
mixture stirred for one hour. The solvent was removed and the residue was 
purified by HPLC eluting with hexane:ether (7:1) giving the desired 
compound as an oil. 
EXAMPLE 25 
7-[[[5-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl-9- 
phenyl-3,5,8-trioxa-4-phosphanonan-1-aminium, 4-oxide, hydroxide, inner 
salt 
A 3.5 g portion of 
3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol, 2.58 
g of 2-bromoethyl phosphorodichlorodate and 1.08 g of triethylamine in 50 
ml of carbon tetrachloride was stirred for 1.5 hours, then filtered and 
the solvent removed. The residue was stirred in a mixture of 100 ml of 
0.5M aqueous sodium acetate and 100 ml of tetrahydrofuran for 1.5 hours, 
then the tetrahydrofuran was removed. The residue was acidified with 
hydrochloric acid and extracted with ether. The ether extract was dried, 
the solvent removed and the residue refluxed in a mixture of 100 ml of 
acetonitrile, 90 ml of methylene chloride and 50 g of trimethylamine for 4 
hours. The solvent was removed and the residue stirred for one hour in a 
mixture of 100 ml of methanol, 4 g of a weak basic ion exchange resin and 
0.7 g of silver carbonate. This mixture was filtered, the solvent removed 
and the residue chromatographed on silica gel, eluting first with 
chloroform:methanol (7:3) to remove the higher Rf components and then with 
chloroform:methanol:water (70:30:5) to elute the product. The solvent was 
removed, giving 3 g of the desired compound as a thick oil. 
EXAMPLE 26 
3-[[3-(Dodecyloxy)-2-methylphenoxy]methyl]-6-hydroxy-N,N,N-trimethyl-1-phen 
yl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner salt 
A mixture of 9.47 g of 
3-[3-(dodecyloxy)-2-methylphenoxy]-2-(phenylmethoxy)-1-propanol, 7.52 g of 
2-bromoethyl phosphorodichlorodate and 3.15 g of triethylamine in 50 ml of 
carbon tetrachloride was stirred for 2 hours, filtered and the solvent 
removed. The residue was stirred in a mixture of 270 ml of 0.5M aqueous 
sodium acetate and 270 ml of tetrahydrofuran for 2 hours. The 
tetrahydrofuran was removed, the residue acidified with hydrochloric acid 
and extracted with ether. The ether extract was evaporated and the residue 
refluxed in a mixture of 250 ml of acetonitrile, 200 ml of chloroform and 
100 g of trimethylamine for 3 hours, then allowed to stand at room 
temperature overnight. The solvent was removed and the residue stirred for 
1.5 hours in 200 ml of methanol containing 8 g of a weak basic ion 
exchange resin and 2 g of silver carbonate. This mixture was filtered and 
the solvent removed. The residue was chromatographed on silica gel eluting 
first with chloroform:methanol (8:2) to remove the higher Rf components 
and then with chloroform:methanol:water (70:30:5) giving 7.2 g of the 
desired compound as an oil. 
EXAMPLE 27 
3-[[[7-(Dodecyloxy)-2-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1- 
phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt 
A mixture of 6.25 g of 
3-[[7-(dodecyloxy)-2-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol, 4.6 g 
of 2-bromoethyl phosphorodichlorodate and 1.93 g of triethylamine in 100 
ml of carbon tetrachloride was stirred for 1.5 hours, filtered and the 
solvent removed. The residue was stirred in a mixture of 180 ml of 0.5M 
aqueous sodium acetate and 180 ml of tetrahydrofuran. The tetrahydrofuran 
was removed, the remainder acidified with hydrochloric acid and ether 
extracted. The ether extract was dried, evaporated and the residue 
refluxed for 3 hours in a mixture of 150 ml of acetonitrile, 120 ml of 
chloroform and 50 g of trimethylamine. The solvent was removed and the 
residue stirred for one hour in 150 ml of methanol containing 1.5 g of 
silver carbonate and 6 g of a weak basic ion exchange resin. This mixture 
was filtered and the solvent removed. The residue was chromatographed on 
silica gel, eluting first with chloroform:methanol (7:3) to remove the 
higher Rf components and then with chloroform:methanol:water (70:30:5), 
giving 4.46 g of the desired compound as an oil. 
EXAMPLE 28 
3-[[[4-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1- 
phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt 
A mixture of 7.3 g of 
3-[[4-(dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol, 5.37 
g of 2-bromoethyl phosphorodichlorodate and 2.25 g of triethylamine in 100 
ml of carbon tetrachloride was stirred for 2 hours, filtered and the 
solvent removed. The residue was stirred for 1.5 hours in a mixture of 180 
ml of 0.5M aqueous sodium acetate and 180 ml of tetrahydrofuran. The 
tetrahydrofuran was removed, the remainder acidified with hydrochloric 
acid and extracted with ether. The ether extract was dried and evaporated, 
giving an oil which crystallized on standing. This solid was added to 150 
ml of acetonitrile, 120 ml of chloroform and 100 g of trimethylamine, 
refluxed for 4 hours and the solvent removed. The residue was stirred in 
200 ml of methanol containing 10 g of a weak basic ion exchange resin and 
1 g of silver carbonate, then filtered and the solvent removed. The 
residue was chromatographed on 200 ml dry volume of silica gel, eluting 
first with chloroform:methanol (7:3) to remove higher Rf impurities and 
then with chloroform:methanol:water (70:30:5) to elute the product. The 
solvent was removed and ether was added, giving 6.5 g of the desired 
compound as a white solid. 
EXAMPLE 29 
3-[[[5-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1- 
phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt 
To 100 ml of carbon tetrachloride was added 6.6 g of 
3-[[6-(dodecyloxy)-2-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol, 4.86 
g of 2-bromoethyl phosphorodichlorodate and 2.03 g of triethylamine. The 
mixture was stirred 3 hours, filtered and the solvent removed. The residue 
was stirred for one hour in a mixture of 180 ml of 0.5M aqueous sodium 
acetate and 180 ml of tetrahydrofuran. The tetrahydrofuran was removed, 
the remainder acidified with hydrochloric acid and extracted with ether. 
The ether extract was dried, evaporated and the residue refluxed for 4 
hours in a mixture of 150 ml of acetonitrile, 120 ml of chloroform and 50 
g of trimethylamine. The solvent was removed and the residue stirred for 2 
hours in 200 ml of methanol containing 1 g of silver carbonate and 8 g of 
a weak basic ion exchange resin. The mixture was filtered, the solvent 
removed and the residue chromatographed on silica gel, eluting first with 
chloroform:methanol (7:3) to remove the higher Rf components and then with 
chloroform:methanol:water (70:30:5), giving 5.42 g of the desired compound 
as a white foam. 
EXAMPLE 30 
3-[[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]methyl]-6-hydroxy-N,N, 
N-trimethyl-1-phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, 
hydroxide, inner salt 
A mixture of 4.5 g of 
3-[2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-2-(phenylmethoxy)-1-p 
ropanol, 2.94 g of 2-bromoethyl phosphorodichlorodate and 1.23 g of 
triethylamine in 100 ml of carbon tetrachloride was stirred for 2 hours, 
filtered and the solvent removed. The residue was stirred for 1.15 hours 
in a mixture of 170 ml of 0.5M aqueous sodium acetate and 170 ml of 
tetrahydrofuran. The tetrahydrofuran was removed, the remainder acidified 
with hydrochloric acid and extracted with ether. The ether extract was 
washed wth water, dried, evaporated and the residue refluxed for 4 hours 
in a mixture of 150 ml of acetonitrile, 120 ml of chloroform and 50 g of 
trimethylamine. The solvent was removed, the residue stirred in 150 ml of 
methanol containing 8 g of a weak basic ion exchange resin and 1 g of 
silver carbonate, filtered and the solvent removed. The residue was 
chromatographed on silica gel eluting first with chloroform:methanol (4:1) 
to remove the higher Rf components and then with chloroform:methanol:water 
(70:30:4), giving 4.61 g of the desired compound as an oil. 
EXAMPLE 31 
2-Bromopropyl-3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)propy 
l phosphoric acid ester 
To a solution of 2.47 g of 2-bromopropyl phosphorodichlorodate in 110 ml of 
carbon tetrachloride, cooled in an ice bath under argon, was added 
dropwise with stirring 5.5 ml of triethylamine. A solution of 3.4 g of 
3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)-1-propanol in 15 
ml of carbon tetrachloride was added dropwise. This mixture was stirred at 
0.degree. C. for 15 minutes, then at room temperature overnight, 110 ml of 
toluene was added and the mixture filtered through diatomaceous earth. The 
solvents were removed and the residual syrup dissolved in 110 ml of 
tetrahydrofuran and 110 ml of 0.5M aqueous sodium acetate, stirred for 2 
hours and the tetrahydrofuran removed in vacuo. The aqueous residue was 
acidified with hydrochloric acid and extracted twice with ether. The ether 
extracts were combined, washed with saturated aqueous sodium chloride, 
dried and evaporated. The resulting syrup was purified by chromatography 
on magnesium silicate, washing with chloroform to remove the mobiles and 
then eluting with 10% methanol in chloroform, giving 3.3 g of the desired 
compound as a syrup. 
EXAMPLE 32 
3-[[[5-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1- 
phenyl-2,5,7-trioxa-6-phosphadecan-9-aminium, 6-oxide, hydroxide, inner 
salt 
A 3.2 g portion of 
2-bromopropyl-3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-2-(phenylmethoxy)prop 
yl phosphoric acid ester was dissolved in 25 ml of cold trimethylamine. A 
15 ml portion of dimethylformamide was added, then 25 ml of 
trimethylamine. This mixture was sealed in a bomb and heated at 
70.degree.-80.degree. C. for 24 hours. The bomb was cooled, opened and the 
solution taken to near dryness. A 20 ml portion of chloroform was added 
followed by 20 ml of methanol, 2 ml of water and 700 mg of silver 
carbonate. The mixture was stirred for 2 hours then filtered through 
diatomaceous earth. The solvents were removed with the exception of 
dimethylformamide and the remainder was evaporated from toluene, again 
with the exception of dimethylformamide. To the cooled remainder was added 
50 ml of trimethylamine. The solution was again sealed in a bomb, heated 
at 80.degree. C. for 30 hours, then allowed to stand at room temperature 
for 72 hours. The bomb was opened, the solution evaporated, 20 ml of 
chloroform, 20 ml of methanol, 2 ml of water and 700 mg of silver 
carbonate were added, the mixture stirred for 2 hours, filtered through 
diatomaceous earth and taken to dryness. A 250 ml of column was prepared 
and charged with silica gel in 10% methanol in chloroform. The column was 
washed with 300 ml of the same solvent system, then the above residue was 
dissolved in the same solvent system and applied to the column. The column 
was eluted in succession with 500 ml of 10% methanol in chloroform, 500 ml 
of 20% methanol in chloroform, then 750 ml of 30% methanol in chloroform 
to remove the mobiles, then eluted with chloroform:methanol:water 
(65:35:6) to elute the product. The product fractions were combined and 
evaporated, giving 1.0 g of the desired compound as a glass. 
EXAMPLE 33 
2-[[[3-[[5-(Dodecyloxy)-1-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosphi 
nyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt 
A mixture of 2.6 g of 
7-[[[5-(dodecycloxy)-1-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl- 
9-phenyl-3,5,8-trioxa-4-phosphanonan-1-aminium, 4-oxide, hydroxide, inner 
salt, 0.5 g of 5% palladium on carbon, 20 ml of glacial acetic acid and 20 
ml of methanol was shaken in a Parr apparatus for 5 hours. The mixture was 
filtered, the solvent removed, ether added and the resulting solid 
collected, giving 2.06 g of the desired compound as a white powder, mp 
45.degree. C. 
EXAMPLE 34 
2-[[[3-[3-(Dodecyloxy)-2-methylphenoxy]-2-hydroxypropoxy]hydroxyphosphinyl] 
oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt 
A mixture of 6.0 g of 
3-[[3-(dodecyloxy)-2-methylphenoxy]methyl]-6-hydroxy-N,N,N-trimethyl-1-phe 
nyl-2,5,7-trioxa-6-phosphanonan-9 -aminium, 6-oxide, hydroxide, inner salt, 
1.3 g of 5% palladium on carbon catalyst, 50 ml of glacial acetic acid and 
50 ml of methanol was shaken in a Parr apparatus for 1.5 hours, then 
filtered through diatomaceous earth. The solvent was removed, toluene 
added and removed and the residue stirred with ether. The resulting solid 
was collected, giving 5.0 g of the desired compound, mp 
97.degree.-101.degree. C. 
EXAMPLE 35 
2-[[[3-[[7-(Dodecyloxy)-2-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosphi 
nyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt 
A mixture of 3.96 g of 
3-[[[7-(dodecyloxy)-2-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1 
-phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt, 0.9 g of 5% palladium on carbon catalyst, 35 ml of glacial acetic 
acid and 35 ml of methanol was shaken in a Parr apparatus for 3 hours and 
then filtered. The solvent was removed and the residue treated with ether, 
giving 3.0 g of the desired compound as a white solid. 
EXAMPLE 36 
2-[[[3-[[4-(Dodecyloxy)-1-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosphi 
nyl]oxy]-N,N,N-triemthylethanaminium, hydroxide, inner salt 
A mixture of 5.0 g of 
3-[[[4-(dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1 
-phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt, 1.1 g of 5% palladium on carbon catalyst, 45 ml of glacial acetic 
acid and 45 ml of methanol was shaken in a Parr apparatus for 4 hours, 
then filtered and the solvent removed. Toluene was added and removed, then 
ether was added and the solid collected, giving 3.5 g of the desired 
compound as a white sticky solid. 
EXAMPLE 37 
2-[[[3-[[6-(Dodecyloxy)-2-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosphi 
nyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt 
A mixture of 4.4 g of 
3-[[[5-(dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1 
-phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, hydroxide, inner 
salt, 1.1 g of 5% palladium on carbon, 45 ml of glacial acetic acid and 45 
ml of methanol was shaken on a Parr apparatus for 5 hours, then filtered. 
The solvent was removed and ether was added, giving 3.3 g of the desired 
compound as a white solid. 
EXAMPLE 38 
2-[[[3-[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-2-hydroxypropoxy] 
hydroxyphosphinyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt 
A mixture of 4.0 g of 
3-[[2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]methyl]-6-hydroxy-N,N 
,N-trimethyl-1-phenyl-2,5,7-trioxa-6-phosphanonan-9-aminium, 6-oxide, 
hydroxide, inner salt, 1.0 g of 5% palladium on carbon, 45 ml of glacial 
acetic acid and 45 ml of methanol was shaken in a Parr apparatus for 3 
hours, then filtered. The solvent was removed, giving 3.49 g of the 
desired compound as a thick oil. 
EXAMPLE 39 
1[[[3-[5-(Dodecyloxy)-1-naphthalenyloxy]-2-hydroxypropoxy]hydroxyphosphinyl 
]oxy]-N,N,N-trimethyl-2-propanaminium, hydroxide, inner salt 
A solution of 940 mg of 
3-[[[5-(dodecyloxy)-1-naphthalenyl]oxy]methyl]-6-hydroxy-N,N,N-trimethyl-1 
-phenyl-2,5,7-trioxa-6-phosphadecan-9-aminium, 6-oxide, hydroxide, inner 
salt in 25 ml of glacial acetic acid and 25 ml of methanol was 
hydrogenated with 0.5 g of 5% palladium on carbon in a Parr apparatus 
overnight. The mixture was filtered, taken to dryness and evaporated twice 
with toluene. The residue was triturated with ether, giving 662 mg of the 
desired compound as a waxy solid. 
EXAMPLE 40 
7-[[[5-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl-9- 
oxo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt 
A mixture of 1.5 g of 
2-[[[3-[[5-(dodecyloxy)-1-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosph 
inyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 6.74 g of 
acetic anhydride and 2.67 g of triethylamine in 75 ml of chloroform was 
refluxed for 4.5 hours. The solvent and excess anhydride were removed at 
reduced pressure. The residue was stirred in ether, giving 1.25 g of the 
desired product, mp 45.degree. C. 
EXAMPLE 41 
7-[[3-(Dodecyloxy)-2-methylphenoxy]methyl]-4-hydroxy-N,N,N-trimethyl-9-oxo- 
3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt 
A mixture of 3.0 g of 
2-[[[3-[3-(dodecyloxy)-2-methylphenoxy]-2-hydroxypropoxy]hydroxyphosphinyl 
]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 14.4 g of acetic 
anhydride and 5.71 g of triethylamine in 200 ml of chloroform was refluxed 
for 4 hours. The solvent and excess anhydride were removed. Toluene was 
added and removed, giving 3.1 g of the desired product as an oil. 
EXAMPLE 42 
7[[[7-(Dodecyloxy)-2-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl-9-o 
xo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt 
A mixture of 2.5 g of 
2-[[[3-[[7-(dodecyloxy)-2-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosph 
inyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 11.24 g of 
acetic anhydride and 4.46 g of triethylamine in 160 ml of chloroform was 
refluxed for 4 hours. The solvent was removed, toluene was added and 
removed twice, then ether was added. The very hygroscopic solid-oil was 
collected, giving the desired product. 
EXAMPLE 43 
7-[[[4-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl-9- 
oxo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt 
A mixture of 2.75 g of 
2-[[[3-[[4-(dodecyloxy)-1-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosph 
inyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 12.36 g of 
acetic anhydride and 4.9 g of triethylamine in 170 ml of chloroform was 
refluxed for 4 hours. The excess anhydride and solvent were removed at 
reduced pressure. Toluene was added and removed several times. Ether was 
added and the resulting solid collected and dried in vacuo, giving the 
desired product as a gum. 
EXAMPLE 44 
7-[[[6-(Dodecyloxy)-2-naphthalenyl]oxy]methyl]-4-hydroxy-N,N,N-trimethyl-9- 
oxo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt 
A mixture of 2.7 g of 
2-[[[3-[[6-(dodecyloxy)-2-naphthalenyl]oxy]-2-hydroxypropoxy]hydroxyphosph 
inyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 12.14 g of 
acetic anhydride and 4.81 g of triethylamine in 170 ml of chloroform was 
refluxed for 4.5 hours. The solvent and excess anhydride were removed, 
toluene was added and removed, then ether was added. The resulting sticky 
solid was collected, giving 2.4 g of the desired product. 
EXAMPLE 45 
7-[[2,4-Bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]methyl]-4-hydroxy-N,N, 
N-trimethyl-9-oxo-3,5,8-trioxa-4-phosphadecan-1-aminium, 4-oxide, 
hydroxide, inner salt 
A mixture of 2.5 g of 
2-[[[3-[2,4-bis(1,1-dimethylethyl)-5-(dodecyloxy)phenoxy]-2-hydroxypropoxy 
]hydroxyphosphinyl]oxy]-N,N,N-trimethylethanaminium, hydroxide, inner salt, 
10.13 g of acetic anhydride and 4.02 g of triethylamine in 170 ml of 
chloroform was refluxed for 4 hours. The solvent and excess anhydride were 
removed and the residue dried in vacuo, giving 2.6 g of the desired 
product as an oil. 
EXAMPLE 46 
4-[[[5-(Dodecyloxy)-1-naphthalenyl]oxy]methyl]-7-hydroxy-N,N,N-trimethyl-2- 
oxo-3,6,8-trioxa-7-phosphaundecan-10-aminium, 7-oxide, hydroxide, inner 
salt 
A mixture of 600 mg of 
1-[[[3-[5-(dodecyloxy)-1-naphthalenyloxy]-2-hydroxypropoxy]hydroxyphosphin 
yl]oxy]-N,N,N-trimethyl-2-propanaminium, hydroxide, inner salt in 30 ml of 
dry chloroform containing 2.63 g of acetic anhydride and 1.04 g of 
triethylamine was stirred at reflux for 5 hours, then taken to dryness. 
The residue was evaporated twice with toluene then chromatographed on a 
silica gel column. The residue was applied in 20% methanol in chloroform. 
The column was eluted with 250 ml of 20% chloroform in methanol, then 250 
ml of 30% methanol in chloroform to remove mobile impurities. The product 
was eluted with chloroform:methanol:water (60:35:6). The 50 ml product 
fractions were combined, evaporated and dried in vacuo, giving 278 mg of 
the desired product. 
The preparation of the compounds of this invention wherein R.sub.3 is a 
benzyloxy group is described hereinbelow in Examples 47-54. 
EXAMPLE 47 
2,2-Dimethyl-4-[[4-(phenylmethoxy)phenoxy]methyl]-1,3-dioxolane 
To a suspension of 18 g of washed (hexane) 50% sodium hydride in 
dimethylformamide was added dropwise a solution of 50.06 g of 
p-(benzyloxy)phenol in dimethylformamide. The mixture was stirred for 1/2 
hour, then a solution of 63 g of the mesylate of solketal in 
dimethylformamide was added. After one hour the mixture was poured onto 
ice and extracted several times with ether. The ether extracts were 
combined, washed with water, dried and the solvents evaporated. The crude 
compound was recrystallized from ether-hexane, giving 21 g of the desired 
compound, mp 87.degree.-89.degree. C. 
EXAMPLE 48 
3-[4-(Phenylmethoxy)phenoxy]-1,2-propanediol 
A mixture of 8.98 g of 
2,2-dimethyl-4-[[4-(phenylmethoxy)phenoxy]methyl]-1,3-dioxolane, 15 g of a 
strongly acidic ion exchange resin and 200 ml of water was refluxed for 24 
hours, then allowed to cool and methylene chloride was added. The mixture 
was filtered and the organic layer separated and saved. The aqueous layer 
was extracted several times with methylene chloride. All organic solutions 
were combined, dried and evaporated, giving 3.0 g of the desired compound, 
mp 125.degree.-127.degree. C. 
EXAMPLE 49 
1-[(4-Methoxyphenyl)diphenylmethoxy]-3-[4-(phenylmethoxy)phenoxy]-2-propano 
To a solution of 18.9 g of 3-[4-(phenylmethoxy)phenoxy]-1,2-propanediol in 
50 ml of pyridine and 24 ml of tetrahydrofuran was added 25.57 g of 
methoxy trityl chloride in several portions. This mixture was stirred for 
24 hours and the solvents removed under reduced pressure. The residue was 
dissolved in chloroform, washed with aqueous sodium bicarbonate, then 
water, dried and evaporated, giving 30 g of the desired compound. 
EXAMPLE 50 
1-[(4-Methoxyphenyl)diphenylmethoxy]-3-[4-(phenylmethoxy)phenoxy]-2-propano 
l, acetate 
A mixture of 18.6 g of 
1-[(4-methoxyphenyl)diphenylmethoxy]-3-[4-(phenylmethoxy)phenox]-2-propano 
l, 20 ml of acetic anhydride and 60 ml of pyridine was stirred under argon 
for 24 hours, then poured onto ice and extracted several times with 
chloroform. The chloroform extracts were combined, washed with aqueous 
sodium bicarbonate, then water, dried and the solvents removed under 
reduced pressure. The residue was coevaporated with toluene, giving 20.4 g 
of the desired compound. 
EXAMPLE 51 
3-[4-(Phenylmethoxy)phenyl]-1,2-propanediol, 2-acetate 
A 17.64 g portion of 
1-[(4-methoxyphenyl)diphenylmethoxy]-3-[4-(phenylmethoxy)phenoxy]-2-propan 
ol, acetate was packed into a boric acid-silicic acid column using 3 liters 
of petroleum ether as eluent. After all the methoxy trityl carbinol was 
eluted, the column was eluted with petroleum ether:ether (9:1), then 
petroleum ether:ether (7:3). The product was isolated and crystallized 
using hexane:ether. 
EXAMPLE 52 
2-(Acetyloxy)-3-[4-(phenylmethoxy)phenoxy]propyl phosphoric acid, 
2-bromoethyl ester 
To a solution of 727 mg of 3-[4-(phenylmethoxy)phenyl]-1,2-propanediol, 
2-acetate in 20 ml of carbon tetrachloride (warmed to 40.degree. C.) was 
added a solution of 662 mg of 2-bromoethyl phosphorodichlorodate in carbon 
tetrachloride followed by 279 mg of triethylamine. The mixture was stirred 
under argon for 3 hours, the filtered through diatomaceous earth. The 
filtrate was concentrated and the residue dissolved in 15 ml of 
tetrahydrofuran. A 15 ml portion of 0.5M aqueous sodium acetate was added, 
the mixture was stirred one hour, brine was added and the mixture 
extracted with three 70 ml portions of ethyl acetate. The organic extracts 
were combined, dried and the solvent evaporated. The residue was purified 
by chromatography on magnesium silicate eluting first with chloroform, 
then with chloroform:methanol (9:1) and finally eluting the product with 
chloroform:methanol (9:2), giving 540 mg of the desired compound, mp 
60.degree. C. 
EXAMPLE 53 
4-Hydroxy-N,N,N-trimethyl-9-oxo-7-[ 
[4-(phenylmethoxy)phenoxy]methyl]-3,5,8-trioxa-4-phosphadecan-1-aminium, 
4-oxide, hydroxide, inner salt 
A mixture of 300 mg of 2-(acetyloxy)-3-[4-(phenylmethoxy)phenoxy]propyl 
phosphoric acid, 2-bromoethyl ester in 15 ml of a solution of 33% 
trimethylamine in acetonitrile was heated to reflux for 16 hours. The 
solvent was removed under reduced pressure and the crude compound purified 
by chromatography on silica gel, eluting first with chloroform, then 
chloroform:methanol (9:1), then chloroform:methanol:water (65:25:1) and 
finally eluting the product with methanol, giving 185 mg of the desired 
compound. 
EXAMPLE 54 
2-(Acetyloxy)-3-[4-(phenylmethoxy)phenoxy]propyl phosphoric acid 
2-bromopropyl ester 
A mixture of 822 mg of 
4-hydroxy-N,N,N-trimethyl-9-oxo-7-[[4-(phenylmethoxy)phenoxy]methyl]-3,5,8 
-trioxa-4-phosphadecan-1-aminium, 4-oxide, hydroxide, inner salt, 930 mg of 
2-bromopropyl phosphorodichlorodate and 384 mg of triethylamine in 8 ml of 
carbon tetrachloride was stirred for 2 hours, filtered through 
diatomaceous earth and the solvent removed. The residue was dissolved in 
10 ml of tetrahydrofuran, 10 ml of 0.5M aqueous sodium acetate was added 
and the mixture was stirred for one hour. The tetrahydrofuran was removed 
and the remainder extracted several times with ethyl acetate. The extracts 
were combined, washed with brine, dried and the solvents evaporated. The 
crude product was purified by chromatography on magnesium silicate, 
eluting first with chloroform and then eluting the product with 
chloroform:methanol (10:1), giving 1.1 g of the desired compound. 
TABLE III 
Alkyl Amines 
trimethyl amine 
dimethyl amine 
methyl amine 
triethyl amine 
diethyl amine 
ethyl amine 
tripropyl amine 
dipropyl amine 
propyl amine 
pyrrolidine 
N-methyl pyrrolidine 
butyl amine 
ammonia