Phosphorus containing compounds as antihypercholesterolemic and antiatherosclerotic agents

Novel phosphorus containing compounds are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful in preventing the intestinal absorption of cholesterol and thus are useful in the treatment of hypercholesterolemia and atherosclerosis.

BACKGROUND OF THE INVENTION 
The present invention relates to novel phosphorus containing compounds 
useful as pharmaceutical agents, to methods for their production, to 
pharmaceutical compositions which include these compounds, and a 
pharmaceutically acceptable carrier, and to pharmaceutical methods of 
treatment. More particularly, the novel compounds of the present invention 
prevent the intestinal absorption of cholesterol in mammals by inhibiting 
the enzyme acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase (ACAT). 
The atheromatous plaque, which is the characteristic lesion of 
atherosclerosis, results from deposition of plasma lipids, mainly 
cholesteryl esters, in the intima of the arterial wall. Progressive 
enlargement of the plaque leads to arterial constriction and ultimately 
coronary heart disease. A number of clinical trials have shown a causal 
relationship between hypercholesterolemia and coronary heart disease. 
Agents that control dietary cholesterol absorption moderate serum 
cholesterol levels. Dietary cholesterol is absorbed from the intestinal 
lumen as free cholesterol which must be esterified with fatty acids. This 
reaction is catalyzed by the enzyme acyl-CoA:cholesterol acyltransferase 
(ACAT). The resulting cholesteryl esters are packaged into the 
chylomicrons which are secreted into the lymph. Inhibitors of ACAT not 
only prevent absorption of dietary cholesterol but also prevent the 
reabsorption of cholesterol which has been released into the intestine 
through endogenous regulatory mechanisms, thus lowering serum cholesterol 
levels and ultimately counteracting the formatting or development of 
atherosclerosis. 
Compounds of the formula 
##STR1## 
wherein R is selected from the group consisting of hydrogen, C.sub.1 
-C.sub.4 alkyl, phenyl, and phenyl substituted with X; X represents one or 
more substituents independently selected from the group consisting of 
hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, 
and nitro; Y represents one or more substituents independently selected 
from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, 
C.sub.1 -C.sub.4 alkoxy, halo, trifluoromethyl, nitro, amino, acetamido, 
acetyl, formyl, cyano, carboxy, C.sub.1 -C.sub.4 carboalkoxy, carboxamido, 
sulfonamido, --CO.sub.2 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, --CO.sub.2 
CH.sub.2 CO.sub.2 CH.sub.3, and --CO.sub.2 CH.sub.2 CO.sub.2 H; and Q is 
selected from the group consisting of C.sub.1 -C.sub.4 alkyl and phenyl 
are disclosed as intermediates to prepare a series of substituted 
aralkanamidobenzoic acids in U.S. Pat. No. 4,536,346. 
A method of controlling undesirable plant growth with a compound of the 
general formula 
##STR2## 
wherein Z.sub.1, Z.sub.2, and Z.sub.3 are independently selected from the 
group consisting of sulfur and oxygen; R.sub.1 is aryl; R.sub.2 is 
selected from the group consisting of alkyl, aralkyl and aryl; R.sub.3 and 
R.sub.4 are independently selected from the group consisting of alkyl, 
hydroxyalkyl, unsubstituted aryl, substituted aryl, alkenyl, aralkyl, and 
hydrogen; provided a maximum of one of R.sub.3 and R.sub.4 is hydrogen. It 
is preferred that R.sub.1 be selected from the group consisting of 
unsubstituted aryl containing six to ten carbon atoms and substituted aryl 
wherein the substituents are selected from the group consisting of alkyl 
containing one to ten carbon atoms, halogen and mixtures thereof; R.sub.2 
be independently selected from the group consisting of alkyl containing 
one to ten carbon atoms, aralkyl containing seven to twenty carbon atoms, 
and aryl containing six to twenty carbon atoms; R.sub.3 and R.sub.4 be 
independently selected from the group consisting of alkyl containing one 
to ten carbon atoms, hydroxyalkyl containing one to ten carbon atoms, 
unsubstituted aryl containing six to ten carbon atoms, substituted aryl 
wherein the substituents are selected from the group consisting of alkyl 
containing one to ten carbon atoms, halogen and mixtures thereof, alkenyl 
containing two to ten carbon atoms, aralkyl containing seven to twenty 
carbon atoms and hydrogen, provided a maximum of one of R.sub.3 and 
R.sub.4 is hydrogen is disclosed in U.S. Pat. No. 3,385,689. 
A process for controlling undesirable plant life with the use of chemical 
compounds of the general formula 
##STR3## 
wherein Z.sub.1, Z.sub.2, and Z.sub.3 are independently selected from the 
group consisting of sulfur and oxygen; R.sub.1 is aryl; R.sub.2 is 
selected from the group consisting of alkyl, aralkyl and aryl; R.sub.3 and 
R.sub.4 are independently selected from the group consisting of alkyl, 
alkylene, acyl, aryl, aralkyl, hydroxyalkyl, alkenyl, cycloalkyl, and 
hydrogen provided that a maximum of one of R.sub.3 and R.sub.4 is 
hydrogen; n is an integer of from 0 to 1; and X is selected from the group 
consisting of oxygen, sulfur, &gt;NY and &gt;CHY wherein Y is selected from the 
group consisting of lower alkyl and hydrogen, provided that when n is 0, 
R.sub.3 and R.sub.4 are selected from the group consisting of alkyl, acyl, 
aryl, aralkyl, hydroxyalkyl, alkenyl, cycloalkyl, and hydrogen provided 
that a maximum of one of R.sub.3 and R.sub.4 is hydrogen and when n is 1, 
R.sub.3 and R.sub.4 are alkylene is disclosed in U.S. Pat. No. 3,449,109. 
A series of compounds of the formula 
##STR4## 
wherein R is independently selected from the group consisting of alkyl, 
alkoxy, hydroxyalkyl, alkenyl, aryl, aralkyl, and cycloalkyl groups and 
hydrogen; R' is independently selected from the group consisting of alkyl, 
hydroxyalkyl, aryl, alkenyl, aralkyl, and cycloalkyl groups and hydrogen, 
provided that a maximum of one of R and R, is hydrogen; Z, Z', and Z" are 
independently selected from the group consisting of oxygen and sulfur; and 
R" and R"' are independently selected from the group consisting of alkyl, 
cycloalkyl, alkoxy, cycloalkoxy, alkylthio, aryl, aryloxy, arylthio, 
aralkyl, aralkoxy, and aralkylthio groups, provided that when one or both 
of R and R' are selected from the group consisting of hydroxyalkyl, 
alkenyl, aryl, aralkyl, and cycloalkyl groups and hydrogen, or R is alkyl, 
R" is selected from the group consisting of alkoxy, aralkoxy, and aryloxy, 
and R"' is aryloxy useful for the control of undesirable plant life is 
disclosed in Canadian Patent 780,800. 
A series of compounds of the formula 
##STR5## 
in which each of R.sub.1, R.sub.2, and R.sub.3 are hydrogen, halogen, 
preferably chlorine, alkyl, preferably of one to four carbon atoms, or 
nitro, R.sub.4 is lower alkyl, preferably with one to four carbon atoms, X 
is oxygen or sulfur and each of A and B is alkyl amino such as mono- and 
dialkyl amino or alkoxy, preferably those where the alkyl is of one to 
four carbon atoms useful as plant growth regulating compounds is disclosed 
in U.S. Pat. No. 3,384,683. 
However, the compounds described in the aforementioned references do not 
disclose or suggest the combination of structural variations nor the use 
in preventing the intestinal absorption of cholesterol of the compounds of 
the present invention described hereinafter. 
SUMMARY OF THE INVENTION 
Accordingly, the present invention is a novel class of compounds of Formula 
I 
##STR6## 
wherein R, R.sup.1, and R.sup.2 are each independently hydrogen, alkyl of 
from one to six carbon atoms, alkoxy of from one to six carbon atoms, 
halogen or trifluoromethyl; 
A is O or NH; 
D is CH.sub.2 or N--R.sup.4 wherein R.sup.4 is hydrogen, alkyl of from one 
to six carbon atoms, or --CH.sub.2 -aryl; 
E is O, CH.sub.2, or N--R.sub.4 wherein R.sup.4 is as defined above; 
n is zero or one; 
X and Y are each independently alkyl of from one to twenty carbon atoms, 
aryl, 
--OR.sup.5 wherein R.sup.5 is 
hydrogen, 
alkyl of from one to twenty carbon atoms, 
--(CH.sub.2)m-aryl wherein m is zero or an integer of 1, 2, or 3 or 
##STR7## 
wherein m is as defined above 
##STR8## 
R.sup.6 wherein R.sup.6 and R.sup.7 are each independently hydrogen, 
alkyl of from one to twenty carbon atoms, 
--(CH.sub.2).sub.o -aryl wherein O is an integer of 1, 2, or 3 or 
##STR9## 
wherein O is as defined above or X and Y are taken together with the 
phosphorus atom to which they are attached to form a ring denoted by 
##STR10## 
wherein R.sup.8 is hydrogen, 
alkyl of from one to twenty carbon atoms, or 
--CH.sub.2 -aryl and R.sup.9 and R.sup.10 are each independently hydrogen, 
alkyl of from one to twenty carbon atoms, or aryl; provided when A is NH, 
D is CH.sub.2, n is zero, and R, R.sup.1, and R.sup.2 are as defined above 
both X and Y are not OR.sup.5 wherein R.sup.5 is alkyl of from one to four 
carbon atoms or phenyl; further provided when A is NH, D is CH.sub.2, E is 
O, n is one and R, R.sup.1, and R.sup.2 are as defined above one of X or Y 
is 
##STR11## 
wherein R.sup.6 and R.sup.7 are as defined above or X and Y are taken 
together with the phosphorus atom to which they are attached to form a 
ring denoted by 
##STR12## 
wherein R.sup.8, R.sup.9, and R.sup.10 are as defined above; and finally 
provided when X and Y are both --OR.sup.5 wherein R.sup.5 is alkyl of from 
one to twenty carbon atoms or 
##STR13## 
wherein R.sup.6 and R.sup.7 are each independently alkyl of from one to 
twenty carbon atoms, A is NH, n is zero and R, R.sup.1 and R.sup.2 are as 
defined above D is N--R.sup.4 wherein R.sup.4 is hydrogen, or --CH.sub.2 
-aryl; or a pharmaceutically acceptable base addition salt thereof. 
Additionally, the present invention is directed to a novel method of 
treating hypercholesterolemia or atherosclerosis comprising administering 
to a mammal in need of such treatment an acyl-coenzyme A:cholesterol 
acyltransferase-inhibitory effective amount of a compound of Formula I in 
unit dosage form. 
Also, the present invention is directed to a pharmaceutical composition for 
treating hypercholesterolemia or atherosclerosis comprising an 
acyl-coenzyme A:cholesterol acyltransferase-inhibitory effective amount of 
a compound of Formula I in combination with a pharmaceutically acceptable 
carrier. 
Finally, the present invention is directed to methods for production of a 
compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of Formula I, the term "alkyl" means a straight or 
branched hydrocarbon radical having from one to twenty carbon atoms and 
includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, 
n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, 
heptadecyl, octadecyl, nonadecyl, eicodecyl, and the like. 
"Alkoxy" is O-alkyl in which alkyl is as defined above. 
"Halogen" is fluorine, chlorine, bromine, or iodine. 
The term "aryl" means an aromatic radical which is a phenyl group or phenyl 
group substituted by one to three substituents selected from alkyl as 
defined above, alkoxy as defined above, halogen as defined above, or 
trifluoromethyl. 
Certain of the compounds of Formula I are capable of further forming 
pharmaceutically acceptable base addition salts. Both of these forms are 
within the scope of the present invention. Pharmaceutically acceptable 
base addition salts are formed with metals or amines, such as alkali and 
alkaline earth metals or organic amines. Examples of metals used as 
cations are sodium, potassium, magnesium, calcium, and the like. Examples 
of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, 
choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine 
(see, for example, Berge, S. M., et al., "Pharmaceutical Salts," Journal 
of Pharmaceutical Science, 66, pp. 1-19 (1977)). 
The base addition salts of said acidic compounds are prepared by contacting 
the free acid form with a sufficient amount of the desired base to produce 
the salt in the conventional manner. The free acid form may be regenerated 
by contacting the salt form with an acid and isolating the free acid in 
the conventional manner. The free acid forms differ from their respective 
salt forms somewhat in certain physical properties such as solubility in 
polar solvents, but otherwise the salts are equivalent to their respective 
free acid for purposes of the present invention. 
Certain of the compounds of the present invention can exist in unsolvated 
forms as well as solvated forms, including hydrated forms. In general, the 
solvated forms, including hydrated forms, are equivalent to unsolvated 
forms and are intended to be encompassed within the scope of the present 
invention. 
Certain of the compounds of the present invention possess one or more 
chiral centers and each center may exist in the R(D) or S(L) 
configuration. The present invention includes all enantiomeric and 
epimeric forms as well as the appropriate mixtures thereof. 
A preferred compound of Formula I is one wherein X and Y are each 
independently aryl, 
--OR.sup.5 wherein R.sup.5 is hydrogen, 
alkyl of from one to twenty carbon atoms, 
--(CH.sub.2).sub.m -aryl wherein m is zero or an integer of 1, 2, or 3, or 
##STR14## 
wherein m is as defined above, 
##STR15## 
wherein R.sup.6 and R.sup.7 are each independently hydrogen, 
alkyl of from one to fifteen carbon atoms, 
--(CH.sub.2).sub.o -aryl wherein O is an integer of 1 or 2, 
##STR16## 
wherein O is zero or an integer of 1 or X and Y are taken together with 
the phosphorus atom to which they are attached to form a ring denoted by 
##STR17## 
wherein R.sup.8 is alkyl of from one to six carbon atoms or 
--CH.sub.2 -aryl and 
R.sup.9 and R.sup.10 are each independently hydrogen, 
alkyl of from one to fifteen carbon atoms or 
aryl; provided when A is NH, D is CH.sub.2, 
n is zero, and R, R.sup.1, and R.sup.2 are as defined above both X and Y 
are not OR.sup.5 wherein R.sup.5 is alkyl of from one to four carbon atoms 
or phenyl; further provided when A is NH, D is CH.sub.2, E is O, n is one 
and R, R.sup.1, and R.sup.2 are as defined above one of X or Y is 
##STR18## 
wherein R.sup.6 and R.sup.7 are as defined above or X and Y are taken 
together with the phosphorus atom to which they are attached to form a 
ring denoted by 
##STR19## 
wherein R.sup.8, R.sup.9, and R.sup.10 are as defined above; and finally 
provided when X and Y are both --OR.sup.5 wherein R.sup.5 is alkyl of from 
one to twenty carbon atoms or 
##STR20## 
wherein R.sup.6 and R.sup.7 are each independently alkyl of from one to 
twenty carbon atoms, A is NH, n is zero and R, R.sup.1 and R.sup.2 are as 
defined above D is N--R.sup.4 wherein R.sup.4 is hydrogen, or --CH.sub.2 
-aryl. 
Another preferred embodiment is a compound of Formula I wherein 
X and Y are each independently aryl, 
--OR.sup.5 wherein R.sup.5 is hydrogen alkyl of from one to fifteen carbon 
atoms, --(CH.sub.2).sub.m -aryl wherein m is zero or an integer of 1 or, 
##STR21## 
wherein R.sup.6 and R.sup.7 are each independently hydrogen, 
alkyl of from one to fifteen carbon atoms, 
--(CH.sub.2).sub.o -aryl wherein O is an integer of 1 or 2, 
##STR22## 
wherein O is zero or an integer of 1 or X and Y are taken together with 
the phosphorus atom to which they are attached to form a ring denoted by 
##STR23## 
wherein R.sup.8 is alkyl of from one to six carbon atoms or --CH.sub.2 
-aryl and 
R.sup.9 and R.sup.10 are each independently hydrogen, 
alkyl of from one to fifteen carbon atoms or aryl; provided when A is NH, 
D is CH.sub.2, n is zero, and R, R.sup.1, and R.sup.2 are as defined above 
both X and Y are not --OR.sup.5 wherein R.sup.5 is alkyl of from one to 
four carbon atoms or phenyl; further provided when A is NH, D is CH.sub.2, 
E is O, n is one and R, R.sup.1, and R.sup.2 are as defined above one of X 
or Y is 
##STR24## 
wherein R.sup.6 and R.sup.7 are as defined above or X and Y are taken 
together with the phosphorus atom to which they are attached to form a 
ring denoted by 
##STR25## 
wherein R.sup.8, R.sup.9, and R.sup.10 are as defined above; and finally 
provided when X and Y are both --OR.sup.5 wherein R.sup.5 is alkyl of from 
one to twenty carbon atoms or 
##STR26## 
wherein R.sup.6 and R.sup.7 are each independently alkyl of from one to 
twenty carbon atoms, A is NH, n is zero and R, R.sup.1 and R.sup.2 are as 
defined above D is N--R.sup.4 wherein R.sup.4 is hydrogen, or --CH.sub.2 
-aryl. 
Particularly valuable are: 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
acid, ethyl ester; 
N-[2,6-Bis(1-methylethyl)phenyl]-2-(diphenylphosphinyl)acetamide; 
(.+-.)-[2-Oxo-2-[2,4,6-trimethoxyphenyl)amino]-ethyl]phenylphosphinic acid, 
ethyl ester; 
(.+-.)-[2-[(2,4-Difluorophenyl)amino]-2-oxoethyl]phenylphosphinic acid, 
ethyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
ethyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
acid; 
(.+-.)-[2-[[2,6-Bis(1 methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
ethyl nonyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(diphenylmeth 
yl)phosphonamidic acid, ethyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N,N-bis(phenylm 
ethyl)phosphonamidic acid, ethyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
acid, 1-methyltridecyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
acid, 1-methylheptyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
acid, dodecyl ester; 
(.+-.)-[[[[[2,6-Bis(1-methylethyl)phenyl]amino]-carbonyl]amino]methyl]phosp 
honic acid, ethyl nonyl ester; 
(.+-.)-[[[[[2,6-Bis(1-methylethyl)phenyl]amino]-carbonyl]amino]methyl]phosp 
honic acid, ethyl diphenylmethyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(2,2-diphenyl 
ethyl)phosphonamidic acid, ethyl ester; 
N-[[[2,6-Bis(1-methylethyl)phenyl]amino]-carbonyl]phosphoramidic acid, 
diethyl ester; 
(Diphenoxyphosphinyl)carbamic acid, 2,6-bis-(1-methylethyl)phenyl ester; 
N-[[[2,6-Bis(1 methylethyl)phenyl]amino]-carbonyl]phosphoramidic acid, 
diphenyl ester; 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic acid, 
4-(hexyloxy)phenyl phenyl ester; 
(.+-.) [[[2,6 Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic acid, 
nonyl phenyl ester; 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl](phenylmethyl)phospho 
ramidic acid, nonyl phenyl ester; 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic acid, 
2,6-bis(1-methylethyl)phenyl nonyl ester; 
(.+-.)-[[[[2,6 
Bis(1-methylethyl)phenyl]amino]carbonyl]methyl]phosphoramidic acid, 
2,6-bis(1-methylethyl)phenyl nonyl ester; 
N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic acid, 
bis(phenylmethyl)ester; 
(4S-cis)-N-[2,6-Bis(1-methylethyl)phenyl]-N'-(3,4-dimethyl-5-phenyl-1,3,2-o 
xazaphosphonolidin-2-yl)urea, P-oxide; 
(.+-.)-N-[[[2,6-Bis(1 
methylethyl)phenyl]amino]carbonyl]-P-decylphosphonamidic acid, ethyl 
ester; 
(.+-.)-[[[(2,4,6-Trimethoxyphenyl)amino]carbonyl]amino]phosphoramidic acid, 
1-methyltridecyl phenyl ester; 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic acid, 
1-methyltridecyl phenyl ester; 
[[[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]amino]methyl]phosphonic 
acid, diethyl ester; 
(.+-.)-N-[2,6-Bis(1-methylethyl)phenyl]-2-[[5-decyl 
-3-(phenylmethyl)-1,3,2-oxazaphosphonolidin-2-yl]oxy]acetamide, P-oxide; 
(.+-.)-N-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-P-phenyl-N-(p 
henylmethyl)phosphonamidic acid, nonyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl](phenylmethyl)ph 
osphoramidic acid, ethyl nonyl ester; 
(.+-.)-N-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphoramidic 
acid, nonyl phenyl ester; 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl](phenylmethyl)phos 
phoramidic acid, nonyl phenyl ester; 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl](phenylmethyl)ph 
osphoramidic acid, 1-methyltridecylphenyl ester; 
[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
bis(phenylmethyl) ester; 
(.+-.)-P-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N,N-dioctyl 
phosphonamidic acid, ethyl ester; and 
(.+-.)-P-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-methyl-N-(2- 
phenylethyl)phosphonamidic acid, ethyl ester; or a pharmaceutically 
acceptable base addition salt thereof. 
The compounds of the present invention are potent inhibitors of the enzyme 
acyl-CoA:cholesteryl acyltransferase (ACAT), and are thus effective in 
inhibiting the esterification and transport of cholesterol across the 
intestinal cell wall. Thus, the compounds of the present invention are 
useful in pharmaceutical formulations for the inhibition of intestinal 
absorption of dietary cholesterol, the reabsorption of cholesterol 
released into the intestine by normal body action, or the modulation of 
cholesterol. 
The ability of representative compounds of the present invention to inhibit 
ACAT was measured using an in vitro test more fully described in Field, F. 
J. and Salome, R. G., Biochemica et Biophysica Acta, Volume 712, pp. 
557-570 (1982). The test assesses the ability of a test compound to 
inhibit the acylation of cholesterol by oleic acid by measuring the amount 
of radiolabeled cholesterol oleate formed from radiolabeled oleic acid in 
a tissue preparation containing rabbit intestinal microsomes. The data in 
Table I is expressed as IC.sub.50 values, i.e., the concentration of test 
compound required to inhibit cholesteryl oleate formation to 50% of 
control. The data in the table shows the ability of representative 
compounds of the present invention to potently inhibit ACAT. 
TABLE 1 
__________________________________________________________________________ 
Biological Activity of Compounds of Formula I 
Example IC.sub.50 
Number 
Compound (.mu.moles) 
__________________________________________________________________________ 
1 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.65 
phenylphosphinic acid, ethyl ester 
2 N-[2,6-Bis(1-methylethyl)phenyl]-2-(diphenylphosphinyl)- 
2.3 
acetamide 
7 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.090 
phosphonic acid, ethyl nonyl ester 
9 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.048 
bis(phenylmethyl)phosphonamidic acid, ethyl ester 
10 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.016 
phenylphosphinic acid, 1-methyltridecyl ester 
11 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.035 
phenylphosphinic acid, 1-methylheptyl ester 
12 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.029 
phenylphosphinic acid, dodecyl ester 
13 (.+-.)-[[[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.28 
amino]methyl]phosphonic acid, ethyl nonyl ester 
18 N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.24 
phosphoramidic acid, diphenyl ester 
19 (.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.41 
phosphoramidic acid, 4-(hexyloxy)phenyl, phenyl ester 
20 (.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.062 
phosphoramidic acid, nonyl phenyl ester 
22 (.+-.)-[[[2,6-Bis(1-methylethyl)phenyl] amino]carbonyl]- 
0.055 
phosphoramidic acid, 2,6-bis(1-methylethyl)phenyl nonyl ester 
24 N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.16 
phosphoramidic acid, bis(phenylmethyl) ester 
25 (4S-cis)-N-[2,6-Bis(1-methylethyl)phenyl]-N'-(3,4-dimethyl-5- 
0.18 
phenyl-1,3,2-oxazaphosphonolidin-2-yl)urea, P-oxide 
26 (.+-.)-N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]-P- 
0.11 
decylphosphonamidic acid, ethyl ester 
27 (.+-.)-[[[(2,4,6-Trimethoxyphenyl)]amino]carbonyl]amino- 
0.063 
phosphoramidic acid, 1-methyltridecyl phenyl ester 
28 (.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]- 
0.036 
phosphoramidic acid, 1-methyltridecyl phenyl ester 
30 (.+-.)-N-[2,6-Bis(1-methylethyl)phenyl]-2-[[5-decyl-3- 
0.033 
(phenylmethyl)-1,3,2-oxazaphosphonolidin-2-yl]oxy]acetamide, 
P-oxide 
31 (.+-.)-N-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-P- 
0.023 
phenyl-N-(phenylmethyl)phosphonamidic acid, nonyl ester 
32 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.014 
(phenylmethyl)phosphoramidic acid, ethyl nonyl ester 
33 (.+-.)-N-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2- 
oxoethyl]phosphoramidic acid, nonyl phenyl ester 
34 (.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.023 
(phenylmethyl)phosphoramidic acid, nonyl phenyl ester 
35 (.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.16 
(phenylmethyl)phosphoramidic acid, 1-methyltridecyl phenyl 
ester 
36 [2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.072 
phosphonic acid, bis(phenylmethyl)ester 
37 (.+-.)-P-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]- 
0.44 
N,N-dioctyl phosphonamidic acid, ethyl ester 
38 (.+-.)-P-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N- 
0.31 
methyl-N-(2-phenylethyl)-phosphonamidic acid, ethyl 
__________________________________________________________________________ 
ester 
##STR27## 
Preferred methods for the preparation of compounds of Formula I are 
described in Schemes I to X. Compounds of Formula I are designated by 
numbers 4, 6, 7, 9, 13, 18, 21, 29, 37, 39, 40, 41, 46, 50, 52, and 52a. 
These schemes illustrate preferred methods from which a person, skilled in 
the art of organic chemistry, could analogously prepare all compounds of 
Formula I. 
Compounds of Formula I designated 4 and 6 are prepared as outlined in 
Scheme I. Thus, a compound of Formula 2 wherein R, R.sup.1, and R.sup.2 
are each independently hydrogen, alkyl of from one to six carbon atoms, 
alkoxy of from one to six carbon atoms, halogen, or trifluoromethyl and A 
is O or NH is reacted with bromoacetyl bromide in the presence of a base 
such as, for example, sodium acetate and the like and a solvent such as, 
for example, acetone and the like to afford a compound of Formula 2 
wherein R, R.sup.1, R.sup.2, and A are as defined above. Reaction of a 
compound of Formula 2 with a compound of Formula 3 wherein R.sup.5a is 
alkyl of from one to twenty carbon atoms, 
--(CH.sub.2).sub.m -aryl wherein m is zero or an integer of 1, 2, or 3 or 
##STR28## 
wherein m is as defined above and Y.sup.a is alkyl of from one to twenty 
carbon atoms, aryl, or --OR.sup.5a wherein R.sup.5a is as defined above 
affords a compound of Formula 4 wherein R, R.sup.1, R.sup.2, A, R.sup.5a, 
and Y.sup.a are as defined above. Reactions of a compound of Formula 2 
with a compound of Formula 5 wherein R.sup.5a is as defined above provided 
alkyl is not one to four carbon atoms or phenyl in the presence of a base 
such as, for example, sodium hydride and the like and a solvent such as, 
for example, tetrahydrofuran and the like affords a compound of Formula 6 
wherein R, R.sup.1, R.sup.2, A, and R.sup.5a are as defined above. 
Compounds of Formula I designated 7 and 9 are prepared as outlined in 
Scheme II. Thus, a compound of Formula 4a wherein R, R.sup.1, R.sup.2, 
R.sup.5a, and Y.sup.a are as defined above is treated with a base such as, 
for example, sodium hydroxide and the like and a solvent such as, for 
example, aqueous ethanol and the like to afford a compound of Formula 7 
wherein R, R.sup.1, R.sup.2, and Y.sup.a are as defined above. Reactions 
of a compound of Formula 7 with a compound of Formula 8 wherein X.sup.a is 
--OR.sup.5a wherein R.sup.5a is as defined above or 
##STR29## 
wherein R.sup.6 and R are each independently hydrogen, 
alkyl of from one to twenty carbon atoms, 
--(CH.sub.2).sub.o -aryl wherein O is an integer of 1, 2, or 3, or 
##STR30## 
wherein O is as defined above provided both X.sup.a and Y.sup.a are not 
OR.sup.5a wherein R.sup.5a is alkyl of from one to four carbon atoms or 
phenyl in the presence of a coupling reagent such as, for example, 
dicyclohexylcarbodiimide and the like and 4-dimethylaminopyridine and a 
solvent such as, for example, pyridine and the like affords a compound of 
Formula 9 wherein R, R.sup.1, R.sup.2, X.sup.a, and Y.sup.a are as defined 
above. 
A compound of Formula I designated as 13 is prepared as outlined in Scheme 
III. Thus, a compound of Formula 10 wherein R.sup.5a is as defined above 
is treated with a compound of Formula 11 wherein R.sup.6 and R.sup.7 are 
as defined above in the presence of a base such as, for example, 
triethylamine and the like and a solvent such as, for example, toluene and 
the like to afford a compound of Formula 12 wherein R.sup.5a, R.sup.6, and 
R.sup.7 are as defined above. Heating a compound of Formula 12 with a 
compound of Formula 2 affords a compound of Formula 13 wherein R, R.sup.1, 
R.sup.2, A, R.sup.5a, R.sup.6, and R.sup.7 are as defined above. 
Compounds of Formula I designated 18 and 21 are prepared as outlined in 
Scheme IV. Thus, a compound of Formula 2a wherein R, R.sup.1, and R.sup.2 
are as defined above is reacted with a compound of Formula 15 in the 
presence of a solvent such as, for example, toluene and the like to afford 
a compound of Formula 15 wherein R, R.sup.1, and R.sup.2 are as defined 
above. Reaction of a compound of Formula 15 in the presence of hydrogen 
and a catalyst such as, for example, palladium on carbon and the like and 
a solvent such as, for example, methanol and the like affords a compound 
of Formula 16 wherein R, R.sup.1, and R.sup.2 are as defined above. 
Reaction of a compound of Formula 16 with a compound of Formula 17 wherein 
Y.sup.a and R.sup.5a are as defined above in the presence of a base such 
as, for example, triethylamine and the like and a solvent such as, for 
example, tetrahydrofuran and the like affords a compound of Formula 18 
wherein R, R.sup.1, R.sup.2, Y.sup.a, and R.sup.5a are as defined above. A 
compound of Formula 19 is reacted first with a compound of Formula 20 
wherein R.sup.5a is as defined above and a base such as, for example, 
triethylamine and the like and a solvent such as, for example, toluene and 
the like followed by reaction with a compound of Formula 15 and a base 
such as, for example, triethylamine and the like and a solvent such as, 
for example, tetrahydrofuran and the like to afford a compound of Formula 
21 wherein R, R.sup.1, R.sup.2, Y.sup.a, and R.sup.5a are as defined 
above. 
A compound of Formula I designated as 29 is prepared as outlined in Scheme 
V. Thus, a compound of Formula 22 wherein R, R.sup.1, and R.sup.2 are as 
defined above is reacted with acetoxyacetyl chloride in a solvent such as, 
for example, toluene and the like to afford a compound of Formula 23 
wherein R, R.sup.1, and R.sup.2 are as defined above. A compound of 
Formula 23 is reacted with a base such as, for example, sodium hydroxide 
and the like and a solvent such as, for example, aqueous methanol and the 
like to afford a compound of Formula 24 wherein R, R.sup.1, and R.sup.2 
are as defined above. A compound of Formula 25 wherein R.sup.10a is alkyl 
of from one to twenty carbon atoms or aryl is reacted with a compound of 
Formula 26 wherein R.sup.8a s alkyl of from one to twenty carbon atoms or 
--CH.sub.2 -aryl in the presence of magnesium perchlorate and a solvent 
such as, for example, acetonitrile and the like to afford a compound of 
Formula 27 wherein R.sup.8a and R.sup.10a are as defined above. Reaction 
of a compound of Formula 27 with phosphorous oxychloride in the presence 
of a base such as, for example, triethylamine and the like and a solvent 
such as, for example, tetrahydrofuran and the like affords a compound of 
Formula 28 wherein R.sup.8a and R.sup.10a are as defined above. Reaction 
of a compound of Formula 28 with a compound of Formula 24 in the presence 
of a base such as, for example, triethylamine and the like and a solvent 
such as, for example, tetrahydrofuran and the like affords a compound of 
Formula 29 wherein R, R.sup.1, R.sup.2, R.sup.8a, and R.sup.10a are as 
defined above. 
A compound of Formula I designated as 37 is prepared as outlined in Scheme 
VI. Thus, a compound of Formula 30 wherein R.sup.5a is as defined above is 
heated with a compound of Formula 31 wherein R.sup.5a is as defined above 
to afford a compound of Formula 32 wherein R.sup.5a is as defined above. 
Reaction of a compound of Formula 32 with a base such as, for example, 
sodium hydroxide and the like and a solvent such as, for example, aqueous 
ethanol affords a compound of Formula 33 wherein R.sup.5a is as defined 
above. Reaction of a compound of Formula 33 with oxalylchloride in the 
presence of a catalytic amount of dimethylformamide and a solvent such as, 
for example, dichloromethane and the like affords a compound of Formula 34 
wherein R.sup.5a is as defined above. Reaction of a compound of Formula 34 
with ammonia in the presence of a solvent such as, for example, toluene 
and the like affords a compound of Formula 35 wherein R.sup.5a is as 
defined above. Reaction of a compound of Formula 35 with a compound of 
Formula 36 wherein R, R.sup.1, and R.sup.2 are as defined above in the 
presence of a base such as, for example, sodium hydride and the like and a 
solvent such as, for example, tetrahydrofuran and the like affords a 
compound of Formula 37 wherein R, R.sup.1, R.sup.2, and R.sup.5a are as 
defined above. 
Compounds of Formula I designated as 39, 40, and 41 are prepared as 
outlined in Scheme VII. Thus, a compound of Formula 38 wherein R.sup.5a is 
as defined above is reacted with a compound of Formula 36 in the presence 
of a solvent such as, for example, ethyl acetate and the like to afford a 
compound of Formula 39 wherein R, R , R.sup.2, and R.sup.5a are as defined 
above. Reaction of a compound of Formula 39 with a base such as, for 
example, sodium hydroxide and the like and a solvent such as, for example, 
aqueous ethanol affords a compound of Formula 40 wherein R, R.sup.1, 
R.sup.2, and R.sup.5a are as defined above. Reaction of a compound of 
Formula 40 with a compound of Formula 8 using the procedure described for 
preparing a compound of Formula 9 from a compound of Formula 8 affords a 
compound of Formula 41 wherein R, R1, R , X.sup.a, and R.sup.5a are as 
defined above. 
A compound of Formula I designated as 46 is prepared as outlined in Scheme 
VIII. Thus, a compound of Formula 20 is reacted with phosphorus 
oxychloride in the presence of a base such as, for example, triethylamine 
and the like and a solvent such as, for example, toluene and the like 
followed by reaction with a compound of Formula 20 wherein the R.sup.5a 
group in the compounds of Formula 20 are not identical to afford a 
compound of Formula 43 in which R.sup.5a is as defined above with the 
proviso that the two R.sup.5a groups are not the same. Alternatively, a 
compound of Formula 42 may be reacted with a compound of Formula 20 as 
described above to afford a compound of Formula 43. Reaction of a compound 
of Formula 43 with a compound of Formula 44 wherein R.sup.4 is hydrogen, 
alkyl of from one to six carbon atoms or --CH.sub.2 -aryl affords a 
compound of Formula 45 wherein R.sup.4 is as defined above and the two 
R.sup.5a groups are as defined above but are not the same. Reaction of a 
compound of Formula 45 with a compound of Formula 36 in the presence of a 
base such as, for example, sodium hydride and the like and a solvent such 
as, for example, tetrahydrofuran and the like affords a compound of 
Formula 46 wherein R, R.sup.1, R.sup.2, R.sup.4, and R.sup.5a are as 
defined above with the proviso that the two R.sup.5a groups are not the 
same and further provided when R.sup.5a is alkyl of from one to twenty 
carbon atoms R.sup.4 is hydrogen or --CH.sub.2 -aryl. 
A compound of Formula I designated as 50 is prepared as outlined in Scheme 
IX. Thus, a compound of Formula 47 wherein R.sup.9 and R.sup.10 are each 
independently hydrogen, alkyl of from one to twenty carbon atoms or aryl 
and R.sup.8a is as defined above is reacted with phosphorus oxychloride in 
the presence of a base such as, for example, triethylamine and the like 
and a solvent such as, for example, toluene and the like to afford a 
compound of Formula 48 wherein R.sup.8a, R.sup.9, and R.sup.10 are as 
defined above. Reaction of a compound of Formula 48 with ammonia in the 
presence of a solvent such as, for example, toluene and the like affords a 
compound of Formula 49 wherein R.sup.8a, R.sup.9, and R.sup.10 are as 
defined above. Reaction of a compound of Formula 49 with a compound of 
Formula 36 in the presence of a base such as, for example, sodium hydride 
and the like and a solvent such as, for example, tetrahydrofuran and the 
like affords a compound of Formula 50 wherein R, R.sup.1, R.sup.2, 
R.sup.8a, R.sup.9, and R.sup.10 are as defined above. 
Compounds of Formula I designated as 52 and 52a are prepared as outlined in 
Scheme X. Thus, a compound of Formula 10 is heated with potassium cyanate 
in a solvent such as, for example, acetone and the like to afford a 
compound of Formula 51 wherein R.sup.5a is as defined above. Reaction of a 
compound of Formula 51 with a compound of Formula 1 affords a compound of 
Formula 52 wherein R, R.sup.1, R.sup.2, A, and R.sup.5a are as defined 
above. Reaction of a compound of Formula 10 with ammonia in the presence 
of a solvent such as, for example, toluene and the like affords a compound 
of Formula 53 wherein R.sup.5a is as defined above. Reaction of a compound 
of Formula 53 with a compound of Formula 36 in the presence of a base such 
as, for example, sodium hydride and the like and a solvent such as, for 
example, tetrahydrofuran and the like affords a compound of Formula 52a 
wherein R, R.sup.1 , R.sup.2, and R.sup.5a are as defined above. 
Compounds of Formulas 1, 3, 5, 8, 10, 11, 14, 17, 19, 20, 22, 25, 26, 30, 
31, 36, 38, 42, and 47 are either known or capable of being prepared by 
methods known in the art. 
The compounds of the present invention can be prepared and administered in 
a wide variety of oral and parenteral dosage forms. It will be obvious to 
those skilled in the art that the following dosage forms may comprise as 
the active component, either a compound of Formula I or a corresponding 
pharmaceutically acceptable salt of a compound of Formula I. 
For preparing pharmaceutical compositions from the compounds of the present 
invention, pharmaceutically acceptable carriers can be either solid or 
liquid. Solid form preparations include powders, tablets, pills, capsules, 
cachets, suppositories, and dispersible granules. A solid carrier can be 
one or more substances which may also act as diluents, flavoring agents, 
solubilizers, lubricants, suspending agents, binders, preservatives, 
tablet disintegrating agents, or an encapsulating material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. 
In tablets, the active component is mixed with the carrier having the 
necessary binding properties in suitable proportions and compacted in the 
shape and size desired. 
The powders and tablets preferably contain from five or ten to about 
seventy percent of the active compound. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, 
starch, gelatin, tragacanth, methylcellulose, sodium 
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The 
term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component, with or without other carriers, is surrounded 
by a carrier, which is thus in association with it. Similarly, cachets and 
lozenges are included. Tablets, powders, capsules, pills, cachets, and 
lozenges can be used as solid dosage forms suitable for oral 
administration. 
For preparing suppositories, a low melting wax, such as a mixture of fatty 
acid glycerides or cocoa butter, is first melted and the active component 
is dispersed homogeneously therein, as by stirring. The molten homogeneous 
mixture is then poured into convenient sized molds, allowed to cool, and 
thereby to solidify. 
Liquid form preparations include solutions, suspensions, and emulsions, for 
example, water or water propylene glycol solutions. For parenteral 
injection liquid preparations can be formulated in solution in aqueous 
polyethylene glycol solution. 
Aqueous solutions suitable for oral use can be prepared by dissolving the 
active component in water and adding suitable colorants, flavors, 
stabilizing, and thickening agents as desired. 
Aqueous suspensions suitable for oral use can be made by dispersing the 
finely divided active component in water with viscous material, such as 
natural or synthetic gums, resins, methylcellulose, sodium 
carboxymethylcellulose, and other well-known suspending agents. 
Also included are solid form preparations which are intended to be 
converted shortly before use to liquid form preparations for oral 
administration. Such liquid forms include solutions, suspensions, and 
emulsions. These preparations may contain, in addition to the active 
component, colorants, flavors, stabilizers, buffers, artificial and 
natural sweeteners, dispersants, thickeners, solubilizing agents, and the 
like. 
The pharmaceutical preparation is preferably in unit dosage form. In such 
form, the preparation is subdivided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of preparation, 
such as packeted tablets, capsules, and powders in vials or ampoules. 
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge 
itself, or it can be the appropriate number of any of these in packaged 
form. 
The quantity of active component in a unit dose preparation may be varied 
or adjusted from 50 mg to 1500 mg preferably 200 mg to 500 mg according to 
the particular application and the potency of the active component. The 
composition can, if desired, also contain other compatible therapeutic 
agents. 
The dosage range for a 70-kg mammal is from about 1 mg/kg to about 100 
mg/kg of body weight per day or preferably about 3 mg/kg to about 15 mg/kg 
of body weight per day when the compounds of the present invention are 
used therapeutically as antihypercholesterolemic and antiatherosclerotic 
agents. The dosages, however, may be varied depending upon the 
requirements of the patient, the severity of the condition being treated, 
and the compound being employed. Determination of the proper dosage for a 
particular situation is within the skill of the art. Generally, treatment 
is initiated with smaller dosages which are less than the optimum dose of 
the compound. Thereafter, the dosage is increased by small increments 
until the optimum effect under the circumstances is reached. For 
convenience, the total daily dosage may be divided and administered in 
portions during the day if desired. 
The following nonlimiting examples illustrate the inventors' preferred 
methods for preparing the compounds of the invention. 
EXAMPLE 1 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]2-oxoethyl]phenylphosphinic 
Acid, Ethyl Ester 
Diethylphenyl phosphonite (1.2 mL, 6.0 mmol) is added to 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide (Example T) (1.2 mL, 6.0 
mmol). The resulting suspension is heated slowly to 150.degree. C. and 
stirred for 3 hours. The liberated ethyl bromide is removed by short-path 
distillation. After cooling, flash chromatography (3:1 ethyl 
acetate/hexane) affords the title compound as a white solid; mp 
170.degree.-173.degree. C. 
EXAMPLE 2 
N-2,6-Bis(1-methylethyl)phenyl-2-(diphenylphosphinyl)acetamide 
In a process analogous to Example 1, using methyldiphenyl phosphinite in 
place of diethyl phenyl phosphonite the title compound is obtained as a 
white powder; mp 210.degree.-212.degree. C. 
EXAMPLE 3 
(.+-.)-2-Oxo-2-[2,4,6-trimethoxyphenyl)amino]ethyl]phenylphosphinic Acid, 
Ethyl Ester 
In a process analogous to Example 1, using 
N-(2,4,6-trimethoxyphenyl)-2-bromoacetamide (Example U) in place of 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide, the title compound is 
obtained as a white solid; mp 118.degree.-120.degree. C. 
EXAMPLE 4 
(.+-.)-[2-(2,4-Difluorophenyl)amino]-2-oxoethyl]phenylphosphinic Acid, 
Ethyl Ester 
In a process analogous to Example 1 using 
N-(2,4-difluorophenyl)-2-bromoacetamide (Example R) in place of 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide, the title compound is 
obtained as a white solid; mp 144.degree.-145.degree. C. 
EXAMPLE 5 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic Acid, 
Ethyl Ester 
Step A: Preparation of 
[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic Acid, 
Diethyl Ester 
In a process analogous to Example 1, using triethyl phosphite in place of 
diethylphenyl phosphonite, the title compound is obtained; mp 
119.degree.-120.degree. C. 
Step B: Preparation of 
(.+-.)-2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic Acid, 
Ethyl Ester 
To a solution of 
[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
diethyl ester (3.0 g, 8.4 mmol) in ethanol (10 mL) is added 2M sodium 
hydroxide (12.7 mL, 25.3 mmol). The solution is stirred for 18 hours at 
room temperature. The solution is diluted with water and chloroform. The 
aqueous phase is acidified to pH 1 with a 10% aqueous solution of 
hydrochloric acid, then extracted three times with chloroform. The 
combined organic extracts are washed with brine, dried over magnesium 
sulfate, and concentrated to afford 2.7 g of the title compound as a white 
foam; mp 162.degree.-165.degree. C. 
EXAMPLE 6 
(.+-.)-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
Acid 
35 In a process analogous to Example 5, using 
(.+-.)-[2-[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl] 
phenylphosphinic acid, ethyl ester in place of 
[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
diethyl ester, the title compound is obtained as the monohydrate; mp 
85.degree.-102.degree. C. 
EXAMPLE 7 
(.+-.)-2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic Acid, 
Ethyl Nonyl Ester 
To a solution of 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic 
acid, ethyl ester (Example 5) (2.0 g, 6.1 mmol) in pyridine (12 mL) at 
0.degree. C. is added 1-nonanol (0.88 g, 6.1 mmol) followed by 
dicyclohexylcarbodiimide (DCC) (1.9 g, 9.2 mmol) and 
4-(dimethylamino)pyridine (0.1 g). The mixture is stirred at 0.degree. C. 
for 30 minutes, then warmed to room temperature and stirred for 72 hours. 
The mixture is diluted with water and chloroform and filtered. The aqueous 
phase is extracted three times with chloroform. The combined organic 
extracts are washed with brine, dried over magnesium sulfate, and 
concentrated. Flash chromatography (3:2 ethyl acetate/hexane) affords a 
semisolid which is taken up in hexane and filtered to remove 
dicyclohexylurea. Concentration of the filtrate affords 1.9 g of the title 
compound as a colorless liquid; infrared spectroscopy (IR) (chloroform 
(CHCl.sub.3)): 2929, 1682, 1024 cm.sup.-1 ; nuclear magnetic resonance 
spectroscopy (.sup. 1 H NMR) (250 MHz, deuterated chloroform 
(CDCl.sub.3)).delta.8.16 (br s, 1 H), 7.33-7.10 (m, 3 H), 4.26-4.05 (m, 4 
H), 3.12 (m, 2 H), 3.06 (d, J=20 Hz, 2 H), 1.70 (m, 2 H), 1.37 (t, J=7 Hz, 
3 H), 1.40-1.10 (m, 12 H), 1.20 (d, J=7 Hz, 12 H), 0.88 (t, J=7 Hz, 3 H); 
Mass spectrum, m/e (relative intensity) 454 (15), 453 (28), 435 (44), 3.10 
(19), 199 (54), 186 (68), 177 (53), 162 (100), 125 (53), 97 (40). 
EXAMPLE 8 
(.+-.)-2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(diphenylmethy 
l)phosphonamidic Acid, Ethyl Ester 
In a process analogous to Example 7, using benzhydrylamine in place of 
1-nonanol, and methylene chloride as solvent in place of pyridine, the 
title compound is obtained; mp 193.degree.-199.degree. C. 
EXAMPLE 9 
(.+-.)-2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N,N-bis(phenylme 
thyl)phosphonamidic Acid, Ethyl Ester 
In a process analogous to Example 7, using dibenzylamine in place of 
1-nonanol, and methylene chloride in place of pyridine, the title compound 
is obtained; mp 128.degree.-129.degree. C. 
EXAMPLE 10 
(.+-.)-2-[[2,6-Bis(1-methylethyl)phenyl]amino2-oxoethyl]phenylphosphinic 
Acid, 1-Methyltridecyl Ester 
In a process analogous to Example 7, using 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphini 
c acid in place of 25 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic 
acid, ethyl ester and 2-tetradecanol in place of 1-nonanol, the title 
compound is obtained as a light yellow oil; IR (film) 3232, 2962, 2925, 
2855, 1684, 1522, 1467, 1217, 987, 968 cm.sup.-1 ; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) (mixture of diastereomers) 8.47 (br s, 1 H), 7.88 (dd, J=13 
and 8 Hz, 2 H), 7.64 7.45 (m, 3 H), 7.30-7.10 (m, 3 H), 4.55-4.30 (m, 1H), 
3.40-3.11 (m, 2 H), 3.35-2.60 (m, 2 H), 1.95-0.90 (m, 28 H), 1.16 (d, J=7 
Hz, 12 H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 
556 (9), 555 (9), 388 (15), 360 (92), 342 (11), 201 (100), 177 (36), 157 
(40), 141 (21), 111 (17), 97 (29). 
EXAMPLE 11 
(.+-.)-2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
Acid, 1-Methylheptyl Ester 
In a process analogous to Example 7, using (.+-.)-[2-[[2,6-bis(1 
methylethyl)phenyl]amino]-2-oxoethyl]phenyl phosphinic acid in place of 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl phosphonic 
acid, ethyl ester and 2-octanol in place of 1-nonanol, the title compound 
is obtained as a white solid; mp 110.degree.-112.degree. C. 
EXAMPLE 12 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic 
Acid, Dodecyl Ester 
In a process analogous to Example 7, using 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenyl 
phosphinic acid in place of 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic 
acid, ethyl ester and 1-dodecanol in place of 1-nonanol, the title 
compound is obtained as a sticky white solid; mp 66.degree.-68.degree. C. 
EXAMPLE 13 
(.+-.)-[[[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]amino]methyl]phosph 
onic Acid, Ethyl Nonyl Ester 
In a process analogous to Example 7, using [[[[[2,6 
bis(1-methylethyl)phenyl]amino]carbonyl]-amino]methyl]phosphonic acid, 
ethyl ester (Example M) in place of 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]-amino]-2-oxoethyl]phosphonic 
acid, ethyl ester, the title compound is obtained as a sticky white solid; 
mp 66.degree.-70.degree. C. 
EXAMPLE 14 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]amino]methyl]phosphon 
ic Acid, Ethyl Diphenylmethyl Ester 
In a process analogous to Example 13, using benzhydrol instead of 
1-nonanol, the title compound is obtained as a white solid; mp 
129.degree.-131.degree. C. 
EXAMPLE 15 
(.+-.)-[2-[[2,6-Bis(1 
methylethyl)phenyl]amino]-2-oxoethyl]-N-(2,2-diphenylethyl)phosphonamidic 
Acid, Ethyl Ester 
To a solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) and 
triethylamine (0.35 mL, 2.5 mmol) in methylene chloride (10 mL) is added 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.48 
g, 2.5 mmol), followed by 
(.+-.)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic 
acid, ethyl ester (Example 5) (0.74 g, 2.3 mmol). 4-Dimethylaminopyridine 
(DMAP) (0.1 g) is added and the solution is stirred for 48 hours at room 
temperature. Additional portions of triethylamine (0.1 mL) and EDCI (0.1 
g) are added and stirring is continued for another 24 hours. The reaction 
mixture is diluted with methylene chloride, washed with water, brine, 
dried over magnesium sulfate, and concentrated. Flash chromatography 
(ethyl acetate) affords 0.22 g of the product as a white solid. 
Recrystallization from ethyl acetate/hexane affords 0.18 g of the title 
compound as a white solid; mp 172.degree.-176.degree. C. 
EXAMPLE 16 
N-[[[2,6-Bis(1-methylethyl)phenyl]amino1carbonyl]phosphoramidic Acid, 
Diethyl Ester 
To a suspension of potassium cyanate (0.82 g, 10.1 mmol) in acetone (10 mL) 
is added diethyl chlorophosphate (1.3 mL, 9.2 mmol). The mixture is heated 
at reflux for 90 minutes. After cooling to room temperature, 
2,6-diisopropylaniline (1.7 mL, 9.2 mmol) is added. The mixture is stirred 
at room temperature for 2 hours, then heated at reflux for 2 hours. After 
cooling, the mixture is filtered. The filtrate is diluted with ethyl 
acetate, washed twice with brine, dried over magnesium sulfate, and 
concentrated. Flash chromatography (3:2 ethyl acetate/hexane) provides 1.3 
g of the product as a white solid. Recrystallization from ethyl 
acetate/hexane provides an analytical sample; mp 157.degree.-158.degree. 
C. 
EXAMPLE 17 
(Diphenoxyphosphinyl)carbamic Acid, 2,6-Bis(1-methylethyl)phenyl Ester 
In a process analogous to Example 16, using 2,6-diisopropylphenol in place 
of 2,6-diisopropylaniline, and diphenyl chlorophosphate in place of 
diethyl chlorophosphate, the title compound is obtained as a white solid; 
mp 132.degree.-135.degree. C. 
EXAMPLE 18 
N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic Acid, 
Diphenyl Ester 
To a suspension of diphenyl phosphoramidate (2.0 g, 8.0 mmol) in 
tetrahydrofuran (20 mL) at 0.degree. C. is added 2,6-diisopropylphenyl 
isocyanate (1.7 mL, 8.0 mmol). Sodium hydride (0.32 g, 8.0 mmol) is then 
added portionwise over 15 minutes. The mixture is allowed to warm to room 
temperature and stirred for 6 hours. The mixture is partitioned between 
ethyl acetate and water and the aqueous phase is extracted three times 
with ethyl acetate. The combined organic extracts are washed with brine, 
dried over magnesium sulfate, and concentrated. Flash chromatography (7:3 
hexane/ethyl acetate) affords 2.4 g of a white solid which is 
recrystallized (ethyl acetate/hexane) to afford 1.6 g of the title 
compound as a white solid; mp 171.degree.-175.degree. C. 
EXAMPLE 19 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic Acid, 
4-(Hexyloxy)phenyl Phenyl Ester 
In a process analogous to Example 18, using (.+-.)-4-(hexyloxy)phenyl 
phenyl phosphoramidic acid (Example A) in place of diphenyl 
phosphoramidate, the title compound is obtained as a white solid; mp 
125.degree.-127.degree. C. 
EXAMPLE 20 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic Acid, 
Nonyl Phenyl Ester 
In a process analogous to Example 18, using (.+-.)-phenyl nonyl 
phosphoramidic acid (Example C) in place of diphenyl phosphoramidate, the 
title compound is obtained as a white solid; mp 108.degree.-112.degree. C. 
EXAMPLE 21 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl](phenylmethyl)phospho 
ramidic Acid, Nonyl Phenyl Ester 
In a process analogous to Example 18, using (.+-.)-N-benzyl phenyl nonyl 
phosphoramidic acid (Example D) in place of diphenyl phosphoramidate, the 
title compound is obtained as a colorless oil; IR (film) 3276, 2961, 2928, 
1701, 1526, 1288, 1025, 937 cm.sup.-1 ; .sup.1 H NMR (250 MHz, 
CDCl.sub.3).delta.9.12 (s, 1 H), 7.44-7.00 (m, 13 H), 5.04 (dd, J=15 and 
11 Hz, 1H), 4.65 (dd, J=15 and 11 Hz, 1 H), 4.14 (m, 1 H), 3.89 (m, 1 H), 
3.09 (m, 1 H), 2.82 (m, 1 H), 1.65-1.45 (m, 2 H), 1.20-1.00 (m, 24 H), 
0.89 (t, J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 593 (21), 
592 (20), 549 (26), 423 (6), 292 (100), 277 (28), 264 (20), 203 (26), 188 
(29), 176 (11), 91 (70). 
EXAMPLE 22 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic Acid, 
2,6-bis(1-methylethyl)phenyl Nonyl Ester 
In a process analogous to Example 18, using 
(.+-.)-[2,6-bis(1-methylethyl)phenyl]nonyl phosphoramidic acid (Example F) 
in place of diphenyl phosphoramidate, the title compound is obtained as a 
waxy, white solid; mp 73.degree.-78.degree. C. 
EXAMPLE 23 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]methyl]phosphoramidic 
Acid, 2,6-Bis(1-methylethyl)phenyl Nonyl Ester 
In a process analogous to Example 18, using (.+-.) 
N-methyl-[2,6-bis(1-methylethyl)phenyl]nonyl phosphoramidic acid (Example 
G) in place of diphenyl phosphoramidate, the title compound is obtained as 
a colorless oil; IR (film) 3280, 2962, 2929, 1705, 1526, 1294, 959 
cm.sup.-1 ; .sup.1 H NMR (250 MHz, CDCl.sub.3).delta.9.25 (s, 1 H), 
7.27-7.02 (m, 6 H), 4.20-4.00 (m, 2 H), 3.47 (m, 2 H), 3.21 (d, J=7 Hz, 3 
H), 3.20-3.03 (m, 2 H), 1.85-1.70 (m, 2 H), 1.50-1.10 (m, 36 H), 0.89 (t, 
J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 602 (36), 601 (97), 
600 (44), 423 (10), 398 (35), 310 (46), 264 (12), 217 (70), 204 (100), 
178 (33), 162 (26), 149 (20). 
EXAMPLE 24 
N-[[[2,6-Bis(1-methylethyl)phenyl]amino1carbonyl]phosphoramidic Acid, 
Bis(phenylmethyl)ester 
In a process analogous to Example 18, using dibenzyl phosphoramidate 
instead of diphenyl phosphoramidate, the title compound is obtained as a 
white powder; mp 136.degree.-138.degree. C. 
EXAMPLE 25 
(4S-cis)-N-[2,6-Bis(1-methylethyl)phenyl]-N'-(3,4-dimethyl-5-phenyl-1,3,2-o 
xazaphosphonolidin-2-yl)urea, P-oxide 
In a process analogous to Example 18, using 
(4S-cis)-2-amino-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine-2-oxide 
(Example H) in place of diphenyl phosphoramidate, the title compound is 
obtained as a white solid; mp 189.degree.-190.degree. C. 
EXAMPLE 26 
(.+-.)-N-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]-P-decylphosphonami 
dic Acid, Ethyl Ester 
In a process analogous to Example 18, using P-decylphosphonamidic acid, 
ethyl ester (Example L) in place of diphenyl phosphoramidate, the title 
compound is obtained as a colorless oil; IR (film) 3246, 2961, 2928, 2856, 
1715, 1522, 1458, 1172, 1039 cm.sup.-1 ; .sup.1 H NMR (250 MHz, 
CDCl.sub.3).delta.8.38 (br s, 1 H), 7.30-7.00 (m, 3 H), 6.60 (br s, 1 H), 
4.30-4.00 (m, 2 H), 3.30-2.95 (m, 2 H), 2.00-1.83 (m, 2 H), 1.80 1.50 (m, 
2 H), 1.50-1.10 (m, 29 H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum, m/e 
(relative intensity) 454 (42), 453 (100), 381 (17), 276 (17), 251 (85), 
223 (80), 203 (70), 177 (67), 162 (65). 
EXAMPLE 27 
(.+-.)-[[[(2,4,6-Trimethoxyphenyl)amino]carbonyl]amino]phosphoramidic Acid, 
1-Methyltridecyl Phenyl Ester 
In a process analogous to Example 18, using (.+-.)-1-methyl tridecyl phenyl 
phosphoramidic acid (Example S) in place of diphenyl phosphoramidate, and 
2,4,6-trimethoxyphenylisocyanate in place of 2,6-diisopropyl phenyl 
isocyanate, the title compound is obtained as a light yellow oil; IR 
(film) 3298, 2920, 2853, 1724, 1695, 1596, 1491, 1206, 950 cm.sup.-1 ; 
.sup.1 H NMR (250 MHz, CDCl.sub.3).delta.7.38-7.10 (m, 6 H), 6.17 (m, 1 
H), 6.11 (s, 2 H), 4.76 (m, 1 H), 3.80 (s, 3 H), 3.75 (s, 6 H), 1.85-1.50 
(m, 4 H), 1.45-1.15 (m, 23 H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum; m/e 
(relative intensity) 579 (7), 578 (6), 405 (4), 383 (29), 289 (4), 222 
(2), 209 (100). 
EXAMPLE 28 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]phosphoramidic Acid, 
1-Methyltridecyl Phenyl Ester 
In a process analogous to Example 18, using (.+-.)-1-methyltridecyl phenyl 
phosphoramidic acid in place of diphenyl phosphoramidate, the title 
compound is obtained as a thick oil; IR (film) 3271, 3061, 2958, 1725, 
1686, 1528, 1491, 1212, 1024, 954 cm.sup.-1 ; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) (mixture of diastereomers).delta.8.33 (br s, .sup.1 H), 
7.40-7.05 (m, 8 H), 6.92 (br s, .sup.1 H), 4.79 (m, .sup.1 H), 3.30-2.70 
(m, 2 H}, 1.80-1.50 (m, 2 H), 1.44 (d, J=6 Hz, 3/2 H), 1.40 (d, J=6 Hz, 3 
H), 1.40-1.00 (m, 32 H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum, m/e 
(relative intensity) 574 (6), 573 (2), 399 (6), 377 (58), 283 (9), 203 
(100). 
EXAMPLE 29 
[[[[[2,6-Bis(1-methylethyl)phenyl]amino]carbonyl]amino]methyl]phosphonic 
Acid, Diethyl Ester 
To a solution of diethyl aminomethyl phosphonate (2.7 g, 16.2 mmol) in 
ethyl acetate at 0.degree. C. is added dropwise 2,6-diisopropylphenyl 
isocyanate (3.5 mL, 16.2 mmol). The solution is allowed to warm to room 
temperature and stirred overnight. After concentration the residue is 
purified by flash chromatography (ethyl acetate) to afford 5.5 g of 
material which is recrystallized from ethyl acetate/hexane to provide 4.6 
g of the title compound as a white solid; mp 132.degree.-134.degree. C. 
EXAMPLE 30 
(.+-.)-N-[2,6-Bis(1-methylethyl)phenyl]2-[[5-decyl-3-(phenylmethyl)-1,3,2-o 
xazaphosphonolidin-2-yl]-oxy]acetamide, P-oxide 
To a solution of 
(.+-.)-2-chloro-5-decyl-3-(phenylmethyl)-1,3,2-oxazaphosphonolidine-2-oxid 
e (Example Q) (0.9 g, 2.4 mmol) in tetrahydrofuran (10 mL) is added 
triethylamine (0.37 mL, 2.7 mmol), followed by N-[2,6 bis(1 
methylethyl)phenyl]-2-hydroxyacetamide (Example 0) (0.57 g, 2.4 mmol). The 
mixture is stirred at room temperature for 48 hours, then filtered and 
concentrated. Flash chromatography (3:2 hexane/ethyl acetate) provides 
0.74 g of the title compound as a semisolid; IR (film) 3239, 2926, 2856, 
1701, 1521, 1457, 1257, 1074 cm.sup.-1 ; .sup.1 H NMR (250 MHz, 
CDCl.sub.3).delta.7.86 (br s, 1 H), 7.37-7.10 (m, 8 H), 4.57 (d, J=9 Hz, 2 
H), 4.29 (dd, J=15 and 9 Hz, .sup.1 H), 4.17 (dd, J=15 and 8 Hz, 1 H), 
3.29 (m, 1 H), 3.12-2.95 (m, 2 H), 1.90-1.40 (m, 2 H), 1.40-1.10 (m, 28 
H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 572 
(16), 571 (40), 274 (75), 204 (86), 188 (57), 160 (40), 146 (45), 120 
(41), 91 (90), 84 (100). 
EXAMPLE 31 
(.+-.)-N-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-P-phenyl-N-(ph 
enylmethyl)phosphonamidic Acid, Nonyl Ester 
To an ice-cooled solution of phenylphosphonic dichloride (1.95 g, 0.01 mol) 
in dry toluene (20 mL) is added triethylamine (1.01 g, 0.01 mol) followed 
by nonyl alcohol (1.45 g, 0.01 mol) in dry toluene (20 mL) dropwise. The 
reaction mixture is stirred for 2 hours in an ice bath and then filtered. 
To this filtrate are added triethylamine (1.01 g, 0.01 mol) and a solution 
of N-[2,6-bis(1-methylethyl)]phenyl-2-[(phenylmethyl)amino]acetamide 
(Example V) (3.24 g, 0.01 mol) in dry tetrahydrofuran (20 mL) and the 
mixture is stirred at room temperature overnight. The reaction mixture is 
filtered and concentrated. Flash chromatography and crystallization 
affords the title compound; IR (KBr) 3212, 2961, 2926, 2868, 2855, 1665, 
1513, .sup.1 H NMR (250 MHz, dimethysulfoxide (DMSO)).delta.9.15 (1 H, s), 
7.90-7.80 (2 H, m), 7.60-7.40 (3 H, m), 7.30-7.00 (8 H, m), 4.42-4.20 (2 
H, m), 4.20-4.00 (2 H, m), 3.90-3.60 (2 H, m), 3.10-2.8 (2 H, m), 
1.80-1.60 (2 H, m), 1.50-1.18 (12 H, m), 1.08 (12 H, d, J=7 Hz), 0.84 (3 
H, t, J=6.5 Hz). 
EXAMPLE 32 
(.+-.)-[2-[[2,6 
Bis(1-methylethyl)phenyl]amino]-2-oxoethyl](phenylmethyl)phosphoramidic 
Acid, Ethyl Nonyl Ester 
In a process analogous to Example 34, using ethyl dichlorophosphate in 
place of phenyldichlorophosphate, the title compound is obtained as a 
colorless oil; IR (film) 3246, 2960, 2926, 1696, 1232, 1029, 950 cm.sup.-1 
; .sup.1 H NMR (250 MHz, CDCl.sub.3).delta.7.86 (br s, 1 H), 7.38-7.10 (m, 
8 H), 4.35 (dd, J=10 and 3 Hz, 2 H), 4.20-3.95 (m, 4 H), 3.80 (d, J=12 Hz, 
2 H), 3.15-2.95 (m, 2 H), 1.75-1.60 (m, 2 H), 1.40-1.15 (m, 27 H), 0.88 
(t, J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 560 (31), 559 
(94), 354 (26), 340 (66), 264 (30), 219 (100), 203 (62), 138 (26), 91 
(81). 
EXAMPLE 33 
(.+-.)-N-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphoramidic 
Acid, Nonyl Phenyl Ester 
In a process analogous to Example 34, using 
N-[2,6-bis(1-methylethyl)phenyl]-2-aminoacetamide (Example W) in place of 
N-[2,6-bis(1-methylethyl)phenyl]-2-(phenylmethyl)aminoacetamide, the title 
compound is obtained as a white solid; mp 88.degree.-90.degree. C. 
EXAMPLE 34 
(.+-.)-[[[2,6-Bis(1-methylethyl)phenyl]amino]2-oxoethyl]-(phenylmethyl)phos 
phoramidic Acid, Nonyl Phenyl Ester 
To an ice-cooled solution of phenyl dichlorophosphate (2.83 g, 0.02 mol) in 
dry toluene (50 mL) is added triethylamine (2.02 g, 0.02 mol) followed by 
nonyl alcohol (2.89 g, 0.02 mol) in dry toluene (40 mL) dropwise. The 
reaction mixture is stirred in an ice bath for 2 hours and then filtered. 
To this filtrate are added triethylamine (2.02 g, 0.02 mol) and a solution 
of N-[2,6-bis(1-methylethyl)phenyl]-2-[phenylmethyl]amino-acetamide 
(Example V) (6.40 g, 0.02 mole) and the mixture is stirred at room 
temperature overnight. The reaction mixture is filtered and concentrated. 
Flash column chromatography and crystallization from ethyl acetate affords 
3.8 g of the title compound; IR (KBr); 3285, 2961, 2925, 2858, 2367, 1684, 
and 1508. .sup.1 H NMR (250 MHz, DMSO).delta.9.22 (1 H, s), 7.44-6.92 (13 
H, m), 4.50-4.30 (2 H, m), 4.30-4.00 (2 H, m), 4.00-3.60 (2 H, m), 
3.10-2.80 (2 H, m), 1.70-1.40 (2 H, m), 1.4-1.18 (12 H, m), 1.18-1.00 (12 
H, d, J=7 Hz), 0.98-0.76 (3 H, m). 
EXAMPLE 35 
(.+-.)-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl](phenylmethyl)ph 
osphoramidic Acid, 1-Methyltridecyl Phenyl Ester 
To an ice-cooled solution of phenyl dichlorophosphate (0.98 g, 0.005 mol) 
in dry toluene (20 mL) is added triethylamine (0.51 g, 0.005 mol) followed 
by 2-tetradecanol (1.07 g, 0.005 mol). The reaction mixture is allowed to 
warm to room temperature and stirred at room temperature overnight. The 
reaction mixture is filtered. To the filtrate are added triethylamine 
(0.51 g, 0.005 mol) and a solution of 
N-[2,6-bis(1-methylethyl)phenyl]-2-[phenylmethyl]amino, acetamide (Example 
V) (1.49 g, 0.005 mol) in dry tetrahydrofuran (20 mL) and the mixture is 
stirred overnight. The reaction mixture is filtered and concentrated. 
Flash column chromatography affords 1.1 g of the title compound as an oil; 
IR (film), 3255, 2960, 2925, 2855, 1696, 1677, 1491. .sup.1 H NMR (250 
MHz, DMSO).delta.9.18 (1 H, s), 7.42-7.00 (13 H, m), 4.75-4.55 (1 H, m), 
4.50-4.25 (2 H, m), 4.00-3.50 (2 H, m), 3.10-2.90 (2 H, m), 1.95-1.12 (25 
H, m), 1.09 (12 H, d, J=7 Hz), 0.85 (3 H, t, J=6.5 Hz). 
EXAMPLE 36 
[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic Acid, Bis 
(Phenylmethyl)ester 
A solution of sodium dibenzylphosphite is prepared by the addition of a 60% 
mineral oil dispersion of sodium hydride (0.4 g, 0.01 mol) to a solution 
of dibenzyl phosphite (2.62 g, 0.01 mol) in dry tetrahydrofuran (20 mL). 
To the resultant solution is added 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide (2.98 g, 0.01 mol) and 
the mixture is stirred at 50.degree. C. overnight. The reaction mixture is 
filtered and concentrated. Flash chromatography and crystallization 
affords 1.4 g of the title compound; mp 117.degree.-119.degree. C. 
EXAMPLE 37 
(.+-.)-P-[2-[[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N,N-dioctyl 
Phosphonamidic Acid, Ethyl Ester 
Step I 
To an ice-cooled solution of dioctylamine (2.42 g, 0.01 mol) is added 
triethylamine (1.01 g, 0.01 mol) followed by diethylchlorophosphite (1.57 
g, 0.01 mol) dropwise and the mixture is allowed to stir for 1 hour. The 
reaction mixture is filtered and concentrated; .sup.1 H NMR (200 MHz, 
CDCl.sub.3).delta.3.9-3.6 (4 H, m), 3.05-2.8 (4 H, m), 1.6-1.00 (30 H, m), 
0.92 (6 H, m). 
Step II 
The crude phosphite (3.25 g) prepared in Step I and 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide (2.68 g, 0.009 mol) are 
heated slowly to 130.degree. C. under a nitrogen atmosphere. The reaction 
mixture is stirred at this temperature for 2 hours. The liberated ethyl 
bromide is removed constantly via a short arm distillation device. The 
reaction mixture is cooled and flash chromatography affords 0.75 g of the 
title compound as an oil; IR (KBr); 3221, 3215, 2959, 2926, 2855, 1679, 
1522; .sup.1 H NMR (250 MHz, CDCl.sub.3).delta.8.50 (1 H, s), 7.38-7.00 (3 
H, m), 4.14-4.85 (2 H, m), 3.4-2.7 (8 H, m), 1.90-1.02 (39 H, m), 
0.98-0.75 (6 H, m). 
EXAMPLE 38 
(.+-.)-P-[2-[2,6-Bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-methyl-N-(2- 
phenylethyl)phosphonamidic Acid, Ethyl Ester 
Step I 
In a process analogous to Step I in Example 37, using N-methyl 
phenethylamine in place of dioctylamine, the phosphite is obtained. 
Step II 
In a process analogous to Step II in Example 41, using the phosphite from 
Step I, affords the title compound as a white solid (0.62 g); mp 
140.degree.-142.degree. C. 
PREATION OF STARTING MATERIALS 
EXAMPLE A 
(.+-.)-4-(Hexyloxy)phenyl Phenyl Phosphoramidic Acid 
To a solution of phenylphosphinic dichloride (2.3 g, 10.9 mmol) and 
triethylamine (1.8 mL, 13.0 mmol) in toluene (15 mL) at 0.degree. C. is 
added dropwise a solution of 4-(hexyloxy)phenol (2.3 g, 11.8 mmol) in 
toluene (5 mL). The mixture is allowed to warm slowly to room temperature 
and stirred for 2 hours. The mixture is filtered. The filtrate is cooled 
to 0.degree. C. and ammonia is bubbled in for 30 minutes. The mixture is 
filtered. The precipitate is suspended in chloroform and stirred for 1 
hour. The mixture is filtered and the filtrate concentrated to afford 2.6 
g of the title compound as a white solid; .sup.1 H NMR (200 MHz, 
CDCl.sub.3) 7.40-7.10 (m, 7 H), 6.85 (d, J=9 Hz, 2 H), 3.92 (t, J=7 Hz, 2 
H), 3.24 (br d, J=6 Hz, 2 H), 1.83-1.65 (m, 3 H), 1.50-1.26 (m, 5 H), 0.91 
(t, J=7 Hz, 3 H). 
EXAMPLE B 
(.+-.)-Phenyl Nonyl Phosphoryl Chloride 
To a solution of phenylphosphonic dichloride (3.0 g, 14.2 mmol) and 
triethylamine (2.4 mL, 17.1 mmol) in toluene (20 mL) at 0.degree. C. is 
added dropwise a solution of 1-nonanol (2.05 g, 14.2 mmol) in toluene (5 
mL). The mixture is allowed to warm slowly to room temperature and stirred 
for 2 hours. The mixture is filtered, and the filtrate is concentrated to 
afford 4.5 g of the title compound as a light yellow liquid; .sup.1 H NMR 
(200 MHz, CDCl.sub.3).delta.7.40-7.15 (m, 5 H), 4.40-4.25 (m, 2 H), 
1.90-1.65 (m, 2 H), 1.45-1.20 (m, 12 H), 0.89 (t, J=7 Hz, 3 H). 
EXAMPLE C 
(.+-.)-Phenyl Nonyl Phosphoramidic Acid 
Ammonia is bubbled into a solution of (.+-.)-phenyl nonyl phosphoryl 
chloride (Example B) (2.5 g, 7.8 mmol) in toluene (20 mL) at 0.degree. C. 
After 5 minutes, the ice bath is removed and the stream of ammonia is 
continued for 10 minutes. The mixture is filtered and concentrated to 
afford 2.2 g of the title compound as a white solid; mp 
64.degree.-65.degree. C. 
EXAMPLE D 
(.+-.) N-Benzyl Phenyl Nonyl Phosphoramidic Acid 
To a solution of (.+-.) phenyl nonyl phosphoryl chloride (Example C) (2.0 
g, 6.3 mmol) in toluene (20 mL) at 0.degree. C. is added a solution of 
benzylamine (0.67 g, 6.3 mmol) and triethylamine (1.3 mL, 9.4 mmol) in 
toluene (5 mL) over 5 minutes. The mixture is allowed to warm to room 
temperature and is stirred for 90 minutes. The mixture is filtered, and 
the filtrate concentrated. Flash chromatography (3:2 hexane/ethyl acetate) 
affords 2.1 g of the title compound as a colorless oil; .sup.1 H NMR (200 
MHz, CDCl.sub.3).delta. 7.40-7.10 (m, 10 H), 4.19 (dd, J=10 and 7 Hz, 2 
H), 4.19-4.05 (m, 2 H), 3.20-3.00 (m, 1 H), 1.70-1.60 (m, 2 H), 1.35-1.20 
(m, 12 H), 0.89 (t, J=7 Hz, 3 H). 
EXAMPLE E 
(.+-.)-[2,6-Bis(1-methylethyl)phenyl]nonyl Phosphoryl Chloride 
To a solution of phosphorus oxychloride (1.53 g, 10.0 mmol) and 
triethylamine (3.5 mL, 25.0 mmol) in toluene (20 mL) at 0.degree. C. is 
added dropwise a solution of 2,6 diisopropylphenol (1.78 g, 10.0 mmol) in 
toluene (5 mL). The mixture is allowed to warm slowly to room temperature 
and stirred for 2 hours. The mixture is cooled to 0.degree. C., and a 
solution of 1-nonanol (1.44 g, 10.0 mmol) in toluene (5 mL) is added 
dropwise. The mixture is allowed to warm to room temperature and stirred 
for 2 hours. The mixture is filtered and the filtrate concentrated to 
afford 4.1 g of a crude oil, which is taken up in 1:1 EtOAc/hexane and 
filtered through a small pad of silica gel. The filtrate is concentrated 
to afford 3.7 g of a light yellow liquid; .sup.1 H NMR (200 MHz, 
CDCl.sub.3).delta.7.17 (br s, 3 H), 4.30-4.10 (m, 2 H), 3.43 (m, 2 H), 
1.85-1.65 (m, 4 H), 1.45-1.10 (m, 10 H), 1.25 (d, J=7 Hz, 12 H), 0.89 (t, 
J=7 Hz, 3 H). 
EXAMPLE F 
(.+-.)-[2,6-Bis(1-methylethyl)phenyl]nonyl Phosphoramidic Acid 
In a process analogous to Example C using 
(.+-.)-[2,6-bis(1-methylethyl)phenyl]nonyl phosphoryl chloride (Example E) 
in place of phenyl nonyl phosphoryl chloride, the title compound is 
obtained as a light yellow liquid; .sup.1 H NMR (200 MHz, 
CDCl.sub.3).delta.7.14 (s, 3 H), 4.09 (q, J=7 Hz, 2 H), 3.50 (m, 2 H), 
2.90 (br s, 2 H), 1.90-1.55 (m, 4 H), 1.30-1.10 (m, 10 H), 1.23 (d, J=7 
Hz, 12 H), 0.89 (t, J=7 Hz, 3 H). 
EXAMPLE G 
(.+-.)-N-methyl [2,6-bis(1-methylethyl)phenyl]nonyl Phosphoramidic Acid 
In a process analogous to Example D, using methylamine in place of 
benzylamine, and (.+-.)-[2,6-bis(1-methylethyl)phenyl nonyl phosphoryl 
chloride in place of (.+-.)-phenyl nonyl phosphoryl chloride, the title 
compound is obtained as a colorless oil after flash chromatography (3:2 
hexane/ethyl acetate); 1 H NMR (200 MHz, CDCl.sub.3).delta.7.13 (s, 3 H), 
4.05-3.98 (m, 2 H), 3.54 (m, 2 H), 2.72 (dd, J=12 and 5 Hz, 3 H), 2.65 (m, 
1 H), 1.70-1.50 (m, 4 H), 1.35-1.15 (m, 10 H), 1.23 (d, J=7 Hz, 12 H), 
0.89 (t, J=7 Hz, 3 H). 
EXAMPLE H 
(4S-cis)-2-Amino-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine-2-oxide 
In a process analogous to Example C, using 
(4S-cis)-2-chloro-3,4-dimethyl-5-phenyloxazaphospholidine-2-oxide in place 
of phenyl nonyl phosphoryl chloride, the title compound is obtained as a 
white solid; mp 170.degree.-172.degree. C. 
EXAMPLE I 
Diethyl-P-decylphosphonate 
In a process analogous to Example 1, using bromodecane instead of 
N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide, the title compound is 
obtained after short-path distillation; bp 130.degree.-135.degree. C./0.1 
mm. 
EXAMPLE J 
P-Decylphosphonic Acid, Ethyl Ester 
In a process analogous to Example 6, using diethyl decylphosphonate 
(Example I) instead of 
[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
diethyl ester, and heating at reflux for 22 hours instead of room 
temperature, the title compound is obtained as a colorless oil; .sup.1 H 
NMR (200 MHz, CDCl.sub.3) 9.30 (br s, .sup.1 H), 4.15-4.00 (m, 2 H), 
1.85-1.50 (m, 4 H), 1.40-1.15 (m, 17 H), 0.88 (t, J=7 Hz, 3 H). 
EXAMPLE K 
P-Decylphosphonyl Chloride, Ethyl Ester 
To a solution of P-decylphosphonic acid, ethyl ester (Example J) (1.2 g, 
4.8 mmol) in methylene chloride (10 mL) at 0.degree. C. is added one drop 
of dimethylformamide. Oxalyl chloride (0.46 mL, 5.3 mmol) is added 
dropwise. The solution is stirred 30 minutes at 0.degree. C., then warmed 
to room temperature and stirred for 4 hours. The mixture is concentrated 
to afford the title compound as a light yellow oil (1.2 g), .sup.1 H NMR 
(90 MHz, CDCl.sub.3).delta.4.40-4.00 (m, 2 H), 2.30-1.15 (m, 21 H), 0.90 
(t, J=7 Hz, 3 H). 
EXAMPLE L 
P-Decylphosphonamidic Acid, Ethyl Ester 
In a process analogous to Example C, using P-decylphosphonyl chloride, 
ethyl ester (Example K) in place of phenyl nonyl phosphoryl chloride, the 
title compound is obtained as a white solid; 1 H NMR (90 MHz, 
CDCl.sub.3).delta.4.05 (p, J=8 Hz, 2 H), 2.90 (br s, 2 H), 1.90-1.10 (m, 
21 H), 0.90 (t, J=7 Hz, 3 H). 
EXAMPLE M 
[[[[[2,6-Bis(1 methylethyl)phenyl]amino]carbonyl]amino]methyl]phosphonic 
Acid, Ethyl Ester 
In a process analogous to Example 6, using [[[[[2,6 
bis(1-methylethyl)phenyl]amino]carbonyl]amino]methyl]phosphonic acid, 
diethyl ester (Example 30) instead of 
[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, 
diethyl ester, the title compound is obtained as a white foam; IR (KBr) 
3374, 2968, 1653, 1559, 1200, 1017 cm.sup.-1 ; .sup.1 H NMR (200 MHz, 
CDCl.sub.3).delta.7.35-7.05 (m, 3 H), 6.40 (m, 1 H), 4.55 (m, 1 H), 
4.20-4.00 (m, 2 H), 3.80-3.60 (m, 2 H), 3.35-3.05 (m, 2 H), 1.35-1.05 (m, 
12 H); Mass spectrum, m/e (relative intensity) 343 (3), 250 (12), 204 
(100), 188 (11), 177 (10), 135 (8). 
EXAMPLE N 
N-[2,6-Bis(1-methylethyl)phenyl]-2-acetoxy Acetamide 
To a solution of acetoxyacetyl chloride (13.5 g, 98.7 mmol) in toluene (70 
mL) at 0.degree. C. is added dropwise via a dropping funnel a solution of 
2,6-diisopropylaniline (17.5 g, 98.7 mmol) and triethylamine (20.6 mL, 
148.1 mmol) in toluene (20 mL). After completion of the addition, the 
mixture is allowed to warm to room temperature and stirred for 24 hours. 
The mixture is filtered through a small pad of silica gel. The filtrate is 
concentrated to afford 11 g of a brown solid. The precipitate is suspended 
in ethyl acetate and stirred overnight. After filtration, the filtrate is 
concentrated to give another 10 g of a brown solid. Recrystallization 
(ethyl acetate/hexane) of the combined material provided 12 g of the title 
compound as an off-white solid; mp 179.degree.-182.degree. C. 
EXAMPLE O 
N-[2,6-Bis(1-methylethyl)phenyl]-2-hydroxyacetamide 
To a solution of N-[2,6-bis(1-methylethyl)phenyl]-2-acetoxyacetamide 
(Example N) (5.7 g, 20.6 mmol) in methanol (50 mL) is added 2M sodium 
hydroxide solution (20 mL). The solution is stirred at room temperature 
for 1 hour. The mixture is concentrated, diluted with water, and extracted 
three times with ethyl acetate. The combined organic extracts are washed 
with brine, dried over magnesium sulfate, and concentrated to afford 4.6 g 
of the title compound as an off-white solid; mp 164.degree.-166.degree. C. 
EXAMPLE P 
1-(N-Benzyl)amino-2-dodecanol 
To a solution of 1,2-epoxydodecane (1.84 g, 10.0 mmol) in anhydrous 
acetonitrile (5 mL) is added anhydrous magnesium perchlorate (2.23 g, 10.0 
mmol). After 15 minutes, benzylamine (1.1 mL, 10.0 mmol) is added dropwise 
and the solution is stirred for 50 hours at room temperature. The mixture 
is concentrated, diluted with water, and extracted twice with ethyl 
acetate. The combined organic extracts are washed with water, brine, dried 
over magnesium sulfate, and concentrated to afford 2.9 g of the title 
compound as a white solid; .sup.1 H NMR (200 MHz, 
CDCl.sub.3).delta.7.38-7.25 (m, 5 H), 3.87 (d, J=2 Hz, 2 H), 3.80-3.65 (m, 
1 H), 3.00-2.75 (m, 3 H), 2.60-2.45 (m, 1 H), 1.40-1.20 (m, 18 H), 0.88 
(t, J=7 Hz, 3 H). 
EXAMPLE Q 
(.+-.)-2-Chloro-5-decyl- 3-(phenylmethyl)-1,3,2-oxazaphosphonolidine 
2-oxide 
To a solution of 1-(N-benzylamino)-2-dodecanol (Example P) (2.0 g, 6.9 
mmol) and triethylamine (3.8 mL) in toluene (20 mL) at 0.degree. C. is 
added dropwise phosphorus oxychloride (0.64 mL, 6.9 mmol). The mixture is 
stirred for 2 hours at 0.degree. C., then filtered through silica gel and 
concentrated to afford 1.9 g of the title compound as a colorless oil; 
.sup.1 H NMR (200 MHz, CDCl.sub.3) (mixture of 
diastereomers).delta.7.40-7.25 (m, 5 H), 4.70-4.45 (m, 1 H), 4.44 (dd, 
J=14 and 10 Hz, 1 H), 3.84 (dd, J=14 and 5 Hz, 1 H), 3.40-3.10 (m, 1 H), 
2.84 (t, J=8 Hz, 1 H), 1.95-1.10 (m, 18 H), 0.88 (t, J=7 Hz, 3 H). 
EXAMPLE R 
N-(2,4-Difluorophenyl)-2-bromoacetamide 
In a process analogous to Example T, using 2,4-difluoroaniline in place of 
2,6-diisopropylaniline, the title compound is obtained as an off-white 
solid; IR (KBr) 3266, 3083, 1661, 1563, 1501, 1432, 1260, 1143, 1095, 853 
cm.sup.-1 ; .sup.1 H NMR (250 MHz, CDCl.sub.3).delta.8.30 (br s, .sup.1 
H), 8.28-8.15 (m, .sup.1 H), 6.91 (t, J=9 Hz, 2 H), 4.05 (s, 2 H); Mass 
spectrum, m/e (relative intensity) 251 (14), 249 (14), 142 (4), 129 (100), 
101 (16). 
EXAMPLE S 
(.+-.)-1-Methyl tridecyl phenyl phosphoramidic acid 
In a process analogous to Example A, using 2-tetradecanol instead of 
4-(hexyloxy)phenol, the title compound is obtained as a white solid; mp 
60.degree.-64.degree. C. (mixture of diastereomers). 
EXAMPLE T 
N-[2,6-Bis(1-methylethyl)phenyl]-2-bromoacetamide 
To a well-stirred ice-cooled mixture of 2,6-diisopropylaniline (10.0 g, 
0.056 mol) in acetone (25 mL) and water (25 mL) and sodium acetate 
trihydrate (15.3 g, 0.112 mol), bromoacetyl bromide (17.0 g, 0.084 mol) is 
added dropwise. The reaction mixture is allowed to warm to room 
temperature and stirred for 1 hour. The reaction mixture is diluted with 
water (100 mL), the product filtered, washed with cold water, sodium 
bicarbonate solution, water, and finally with hexane. The product is dried 
in a vacuum at 40.degree. C. to afford 14.5 g of the title compound as a 
white solid; mp I70.degree. C. 
EXAMPLE U 
N-(2,4,6-Trimethoxyphenyl)-2-bromoacetamide 
In a process analogous to Example T using 2,4,6-trimethoxyaniline in place 
of 2,6-diisopropylaniline, the title compound is obtained as a solid; mp 
160.degree.-161.degree. C. 
EXAMPLE V 
N-2,6-Bis(1-methylethyl)phenyl]-2-(phenylmethyl)amino]acetamide 
To a stirred solution of benzylamine (6.43 g, 0.06 mol) in toluene (75 mL) 
is added N-[2,6-bis(1-methylethyl)phenyl]-2-bromoacetamide (8.95 g, 0.03 
mol) and then refluxed for 2 hours. The reaction mixture is filtered and 
concentrated. Flash column chromatography and crystallization affords 6.4 
g of the title compound; .sup.1 H NMR (250 MHz, CDCl.sub.3).delta.8.73 (1 
H, s , 7.40-7.04 (8 H, m), 3.93 (2 H, s), 3.53 (2 H, s), 3.05-2.95 (2 H, 
m), 2.00 (1 H, br s , 1.18 12 H, d, J=6.8 Hz). 
EXAMPLE W 
N-[2,6-Bis(1-methylethyl)phenyl]-2-aminoacetamide 
To a solution of 
N-[2,6-bis(1-methylethyl)phenyl]-2-[(phenylmethyl)amino]acetamide (Example 
V) (0.80 g, 2.5 mmol) in methanol (10 mL) is added 20% Pd/C (0.1 g). The 
mixture is stirred under an atmosphere of hydrogen for 20 hours. After 
filtration and concentration, flash chromatography (ethyl acetate) affords 
0.47 g of the title compound as a white solid; mp 88.degree.-95.degree. C.