Aminophosphonates in the synthesis of new radioprotecting agents

Article abstract of DOI:10.1023/A:1019671324617

Reactions of bis(trimethylsilyl) hydrogen phosphite with Schiff bases derived from indole-3-carbaldehyde and aniline or ethyl p-aminobenzoate, as well as of diisopropyl hydrogen phosphite with N-benzylideneaniline, gave water-soluble sodium salts of α-aminophosphonic acids which are potential radioprotecting agents.

Full text of DOI:10.1023/A:1019671324617

Russian Journal of Organic Chemistry, Vol. 38, No. 5, 2002, pp. 723 725. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 5, 2002,
pp. 760 762.
Original Russian Text Copyright
2002 by Sal’keeva, Nurmaganbetova, Kurmanaliev, Gazizov.
Aminophosphonates in the Synthesis
of New Radioprotecting Agents
L. K. Sal’keeva, M. T. Nurmaganbetova, O. Sh. Kurmanaliev, and T. Kh. Gazizov
Buketov Karaganda State University, ul. Universitetskaya 28, Karaganda, 470074 Kazakhstan
Received February 23, 2001
Abstract Reactions of bis(trimethylsilyl) hydrogen phosphite with Schiff bases derived from indole-3-
carbaldehyde and aniline or ethyl p-aminobenzoate, as well as of diisopropyl hydrogen phosphite with
N-benzylideneaniline, gave water-soluble sodium salts of -aminophosphonic acids which are potential
radioprotecting agents.
Search for compounds possessing radioprotective
properties constitutes an extensively developing field
of chemistry. More than 50 years elapsed since the
possibility for chemical protection from ionizing
radiation was demonstrated for the first time. During
this period, much efforts were made to synthesize
and study prophylactic effect of thousands of com-
pounds (including those of natural origin) possessing
radioprotective properties. Among these, quite
efficient radioprotectors of the indolylalkylamine
preventing death of a considerable part of animals
exposed to X-ray and -radiation. However, high
toxicity and narrow range of therapic effect of the
known radioprotectors stimulate search for new more
efficient compounds.
A large group of radioprotecting agents includes
aminoalkyl thiophosphoric derivatives (such as Cysta-
phos and Gammaphos) and also nitrogen-containing
heterocycles, in particular indolylalkylamines. With
the goal of searching for new efficient radioprotectors
series have been found [1, 2], which are capable of we focused on aminophosphonic acid derivatives
Scheme 1.
I, R = COOEt; II, R = H.
Scheme 2.
1070-4280/02/3805-0723$27.00 2002 MAIK Nauka/Interperiodica

724
SAL’KEEVA et al.
Scheme 3.
V, VII, R = COOEt; VI, VIII, R = H.
whose structural fragments, specifically, P C N and
P C N P, are known as carriers of radioprotective
properties. As starting compounds we chose Schiff
bases I and II which were synthesized by condensa-
tion of indole-3-carbaldehyde with aniline and ethyl
p-aminobenzoate, respectively, according to standard
procedure (Scheme 1). Compounds I and II are stable
crystalline substances. They were brought into reac-
tion with bis(trimethylsilyl) hydrogen phosphite in
dry benzene to obtain phosphonates III and IV
(Scheme 2). The progress of the reaction was moni-
tored by 31P NMR and IR spectroscopy. Crystalline
phosphonates III and IV separated from the benzene
solution. They were treated with 2 equiv of methanol,
and phosphonic acids V and VI were converted into
water-soluble sodium salts VII and VIII by the action
of sodium hydrogen carbonate (Scheme 3).
hydrolysis of phosphonate IX in 5 M hydrochloric
acid. Phosphorylation of IX with diethyl phosphoro-
chloridite in the presence of triethylamine as hydrogen
chloride acceptor afforded phosphonate X having
a P C N P fragment. Compound X was treated
with molecular sulfur to obtain thiophosphonate XI
(Scheme 5).
Scheme 5.
The IR spectra of sodium salts VII and VIII
1
contain absorption bands typical of P C (750 cm ),
The 31P NMR spectrum of diethyl N-( -diisopro-
poxyphosphinoylbenzyl)-N-phenylamidophosphoro-
1
1
P O (1100 cm ), C O C (1280 1290 cm ),
1
1
C Carom (1460 1470 cm ), C N (1550 1570 cm ),
thioate (XI) contained signals at
26 and 80 ppm,
1
1
which were split with a constant JPP, P of 20 Hz.
C O (1695 cm ), O H (2700 2500 cm , br), and
1
NH (3300 cm ) groups and bonds. In the 31P NMR
spectra of aqueous solutions of VII and VIII signals
EXPERIMENTAL
at
40.75 and 40.47 ppm were observed, which cor-
respPond to phosphonate groups.
The 31P NMR spectra were recorded on a KGU-4
instrument at 10.2 MHz; the chemical shifts were
measured relative to 85% H3PO4. The IR spectra were
obtained on a UR-20 spectrometer in KBr.
In order to synthesize compounds having a poten-
tially radioprotective P N C P fragment we per-
formed the reaction of N-benzylideneaniline with
diisopropyl hydrogen phosphite (Scheme 4).
Reaction of indole-3-carbaldehyde with ethyl
p-aminobenzoate. An Arbuzov flask was charged
with 7.5 g of indole-3-carbaldehyde and 8.25 g
(5% excess) of ethyl p-aminobenzoate, and the mix-
ture was heated at 90 100 C under reduced pressure
(water-jet pump). Liberation of water was observed.
When the reaction was complete ( 2 h), excess ethyl
p-aminobenzoate was removed at 78 80 C (1 mm),
and the residue was washed with petroleum ether.
The precipitate was filtered off and recrystallized
from benzene. We thus obtained 8.74 g (65%) of
ethyl N-(3-indolylmethylene)-p-aminobenzoate (I),
mp 176 177 C. Found, %: C 73.42; H 5.71; N 9.41.
C18H16N2O2. Calculated, %: C 73.97; H 5.48; N 9.59.
Scheme 4.
The product was aminophosphonate IX which
showed a signal at
22 ppm in the 31P NMR spec-
P
trum. Its IR spectrum contained the following bands,
, cm : 760 (P C), 1030 (P O C), 1240 (P O),
1510 (C N), 1500 and 1530 (C Carom), 3300 (NH).
We failed to obtain the desired phosphonic acid by
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002

AMINOPHOSPHONATES IN THE SYNTHESIS OF NEW RADIOPROTECTING AGENTS
725
Reaction of indole-3-carbaldehyde with aniline.
An Arbuzov flask was charged with 4.32 g of indole-
3-carbaldehyde and 15.33 g (5 equiv) of aniline. The
mixture was heated under reduced pressure (10 mm).
The reaction was accompanied by liberation of water.
After 2 h, the mixture was treated with petroleum
ether, and light yellow crystals separated from the
dark mixture. The crystals were filtered off and re-
crystallized from benzene to obtain 3.67 g (59%) of
N-(3-indolylmethylene)aniline (II), mp 127 128 C.
Found, %: C 81.24; H 5.98; N 12.38. C15H12N2.
Calculated, %: C 81.82; H 5.45; N 12.73.
Reaction of Schiff base I with bis(trimethylsilyl)
hydrogen phosphite. A mixture of 3.21 g of Schiff
base I and 2.49 g of bis(trimethylsilyl) hydrogen
phosphite in 50 ml of benzene was heated for 4 5 h
at 70 80 C. The mixture was treated with petroleum
ether to isolate 2.22 g (59%) of bis(trimethylsilyl)
3-indolyl(p-ethoxycarbonylphenylamino)methylphos-
phonate (III), mp 109 110 C. Found, %: C 55.43;
H 6.37; N 5.28; P 6.02. C24H35N2O5PSi2. Calculated,
%: C 55.60; H 6.76; N 5.41; P 5.98.
Reaction of Schiff base II with bis(trimethyl-
silyl) hydrogen phosphite. A mixture of 3.28 g of
bis(trimethylsilyl) hydrogen phosphite and 3.2 g of
Schiff base II in 50 ml of benzene was heated for
2 h at 70 80 C. The precipitate was washed with
petroleum ether. Yield 4.5 g (69%) of bis(trimethyl-
silyl) 3-indolyl(phenylamino)methylphosphonate (IV),
mp 201 202 C. Found, %: C 56.23; H 6.48; N 6.08;
P 7.15. C21H31N2O3PSi2. Calculated, %: C 56.50;
H 6.95; N 6.28; P 6.95.
Reaction of phosphonate III with methanol.
Methanol, 10 ml, was added to 2.12 g of phosphonate
III, and the mixture was heated for 5 6 h at 60 70 C.
Excess methanol and liberated methyl trimethylsilyl
ether were distilled off to obtain 1.4 g (93%) of
3-indolyl(p-ethoxycarbonylphenylamino)methylphos-
phonic acid (V), mp 79 80 C. Found, %: C 57.48;
H 5.33; N 7.81; P 8.11. C18H19N2O5P. Calculated, %:
C 57.75; H 5.08; N 7.49; P 8.29.
under vigorous stirring, maintaining the pH at a value
of 7. After 2 h, the mixture was filtered, and the
filtrate was evaporated to obtain 1.2 g (76%) of
disodium 3-indolyl(p-ethoxycarbonylphenylamino)-
methylphosphonate (VII), mp 71 72 C. Found, %:
C 51.98; H 4.33; N 6.42; P 7.66. C18H17N2Na2O5P.
Calculated, %: C 51.67; H 4.07; N 6.70; P 7.42.
Reaction of phosphonic acid VI with sodium
hydrogen carbonate. Water, 10 15 ml, was added
to 2.14 g of acid VI, and a solution of 1.2 g of
NaHCO3 in 50 ml of water was added dropwise. The
mixture was treated as described above to obtain 2.1 g
(87%) of disodium 3-indolyl(phenylamino)methyl-
phosphonate (VIII), mp 219 220 C. Found, %:
C 52.62; H 3.78; N 8.41; P 8.71. C15H13N2Na2O3P.
Calculated, %: C 52.02; H 3.76; N 8.09; P 8.96.
Reaction of N-benzylideneaniline with diiso-
propyl hydrogen phosphite. A mixture of 5.4 g of
N-benzylideneaniline and 5.2 g (5% excess) of diiso-
propyl hydrogen phosphite was heated for 2 3 h on
a water bath. After cooling, the colorless crystals
were filtered off and washed with ether. Yield 6.2 g
(59%) of diisopropyl -(phenylamino)benzylphospho-
nate (IX), mp 96 C. Found, %: C 65.28; H 7.23;
N 4.48; P 8.71. C19H26NO3P. Calculated, %: C 65.71;
H 7.49; N 4.03; P 8.93.
Reaction of phosphonate IX with diethyl phos-
phorochloridite. Diethyl phosphorochloridite, 0.86 g,
was added dropwise with stirring to a mixture of 1.9 g
of phosphonate IX and 1.04 g of triethylamine in dry
diethyl ether. The precipitate of triethylamine hydro-
chloride was filtered off, and the solvent was removed
from the filtrate to obtain 1.7 g (65%) of diisopropyl
-(N-diethoxyphosphino-N-phenylamino)benzylphos-
phonate (X), mp 99 C. Found, %: C 59.67; H 7.89;
N 2.75; P 13.59. C23H35NO5P2. Calculated, %:
C 59.10; H 7.49; N 2.99; P 13.28.
Reaction of phosphonate X with elemental
sulfur. A mixture of 1.5 g of compound X and 0.1 g
of powdered sulfur was heated for 3 h at 80 C. The
mixture was dissolved in ether, and the solvent was
distilled off to obtain 0.9 g of diethyl N-( -diiso-
propoxyphosphinoylbenzyl)-N-phenylamidophos-
phorothioate (XI), mp 115 C. Found, %: C 55.78;
H 7.49; N 2.47; P 12.88; S 6.22. C23H35NO5P2S. Cal-
culated, %: C 55.31; H 7.01; N 2.81; P 12.42; S 6.41.
Reaction of phosphonate IV with methanol.
Methanol, 50 ml, was added to 4.0 g of compound
IV, and the mixture was heated for 2 h at 80 90 C.
Excess methanol and liberated methyl trimethylsilyl
ether were distilled off to obtain 2.5 g (93%) of
3-indolyl(phenylamino)methylphosphonic acid (VI),
mp 209 210 C. Found, %: C 59.23; H 5.12; N 9.12;
P 10.48. C15H15N2O3P. Calculated, %: C 59.60;
H 4.97; N 9.27; P 10.26.
REFERENCES
1. Yashchunskii, V.G., Usp. Khim., 1975, vol. 44, no. 3,
pp. 531 574.
Reaction of phosphonic acid V with sodium
hydrogen carbonate. Water, 10 ml, was added to
1.4 g of phosphonic acid V, and a solution of 0.62 g
of NaHCO3 in 30 ml of water was added dropwise
2. Belen’kaya, I.L., Slavachevskaya, I.M., Strel’ni-
kov, Yu.E., and Prosypkina, A.P., Khim.-Farm. Zh.,
1978, vol. 10, no. 12, pp. 25 34.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002