Synthesis of phosphonoindoprofen

Article abstract of DOI:10.1080/10426500903567547

Two synthetic routes to phosphonic analogues of indoprofen, a nonsteroidal anti-inflammatory drug, were developed by the cyclization of aniline 2 (method A) and by the Arbuzov reaction of corresponding alkylchloride 3 with triethylphosphite (method B). Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Phosphonoindoprofen
Georgiy O. Kachkovskyi a & Oleg I. Kolodiazhnyi a
a Institute of Bioorganic Chemistry and Petrochemistry of the
National Academy of Sciences of Ukraine, Kyiv, Ukraine
Version of record first published: 05 Nov 2010.
To cite this article: Georgiy O. Kachkovskyi & Oleg I. Kolodiazhnyi (2010): Synthesis of
Phosphonoindoprofen, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:11, 2238-2242
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Phosphorus, Sulfur, and Silicon, 185:2238–2242, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903567547
SYNTHESIS OF PHOSPHONOINDOPROFEN
Georgiy O. Kachkovskyi and Oleg I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrochemistry of the National Academy
of Sciences of Ukraine, Kyiv, Ukraine
Two synthetic routes to phosphonic analogues of indoprofen, a nonsteroidal anti-
inflammatory drug, were developed by the cyclization of aniline 2 (method A) and by the
Arbuzov reaction of corresponding alkylchloride 3 with triethylphosphite (method B).
Keywords Indoprofen; isoindolin-1-ones; phosphonic acids
INTRODUCTION
Indoprofen (Figure 1) is a nonsteroidal anti-inflammatory drug of the 2-arylpropionic
acids (profens) family.1 The most prominent members of this group of drugs are ibupro-
fen, naproxen, ketoprofen, and suprofen. Indoprofen is a highly effective drug for use in
rheumatoid arthritis, osteoarthritis, and postoperative pain. It increases the production of
the SMN-protein, a lack of which causes development of spinal muscular atrophy (SMA),
a muscle-wasting and often life-threatening childhood disease.2–4 However, indoprofen has
serious side effects (i.e., gastrointestinal bleeding).1–4 Therefore, it was important to study
analogues of indoprofen that might be effective and well tolerated. In connection with
our ongoing program on the syntheses of phosphorous analogues of bioactive and natural
compounds,5–7 we have prepared a phosphonic analogue of indoprofen, taking into account
an idea that phosphonates can serve as bioisosters of carboxylic acids.8,9 The phosphonoin-
doprofen 1а was not earlier reported, though phosphonic analogues of some other profens,
for example phosphonaproxen, have been described.10,11
RESULTS AND DISCUSSION
The diethyl phosphonoindoprofen 1b was prepared by two methods: by cycliza-
tion of para-substituted aniline 212 (method A) and by Arbuzov reaction of chloride
313 with triethylphosphite (method B). The reaction of aniline 2 with methyl ortho-
brommethylbenzoate 414–19 led first to N-alkylated product 5, which was then cyclizated
Received 19 November 2009; accepted 17 December 2009.
This work was supported by the STCU grant no. 3558.
Address correspondence to Oleg I. Kolodiazhnyi, Institute of Bioorganic Chemistry and Petrochemistry of
the National Academy of Sciences of Ukraine, Murmanska Str, 1, Kyiv 02094, Ukraine. E-mail: olegkol321@
rambler.ru
2238

SYNTHESIS OF PHOSPHONOINDOPROFEN
2239
CH3
CH3
N
N
COOH
P(O)(OR)2
O
O
1a R = H
1b R = Et
Indoprofen
Figure 1 Structures of indoprofen and phosphonoindoprofen.
into isoindolone 1b (Scheme 1). The conversion of 5 into phosphonoisoindolone 1b
essentially depended on the nature of the base and the solvent, and in all cases resulted in
mixture of 1b and 5. The highest ratio of products (5:1) was obtained when initial aniline
2 was used as a base. The diethyl phosphonoindoprofen 1b was purified by crystallization
from hexane and obtained as a colorless solid in a yield of 40% (Table I).
(EtO)3P
CH3
Cl
150 o
C
CH3
Me3SiBr
MeOH
N
N
1a
N
+
P(O)(OR)2
-(EtO)2P(O)Et
O
O
O
3
6
1b
Scheme 1 Synthesis of the phosphonoindoprofen 1a by method B.
The subsequent treatment of ester 1b with trimethylsilylbromide and methanol pro-
vided the phosphonoindoprofen 1a in an almost quantitative yield, which was isolated as
a pale powder with a melting point of 227–228◦C. This compound is slightly soluble in
water, but readily soluble in organic solvents such as ethanol.
The Arbuzov reaction of sec-alkylchloride 3 with excess of triethylphosphite at 160 ◦C
for 16 h led to the formation of products 1b and 6 in 4/1 ratio.20 Crystallization from hexane
gave the pure diethyl phosphonoindoprofen 1b in yield of 32% (Scheme 1). After treatment
Table I Synthesis of the phosphonoindoprofen 1a by method A
O
P(OEt)2
CH3
CH3
Me3SiBr
B
CH3
B
Br
N
H
+
1a
N
P(O)(OEt)2
MeOH
P(O)(OEt)2
COOMe
H2N
COOMe
O
2
4
5
1b
Entry
Solvent
B (n-fold excess)
Temp (◦С)
Time (h)
1b∗ (conversion,%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
Pyridine
THF
MeOH
n-PrOH
EtOH
K2CO3 (6)
K2CO3 (6)
Cs2CO3 (10)
Pyridine
NaH (2.5)
Et3N (4)
75
100
90
115
18
65
97
78
60
60
60
16
16
60
60
60
75
75
0
75
66
25
75
83
i-Pr2NEt (3)
2 (3)
∗According to 1Н NMR spectra.

2240
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
of the ester 1b with trimethylsilylbromide and methanol, the phosphonoindoprofen 1a was
obtained in excellent yield.
In conclusion, we have described two alternative synthetic routes to a phosphonic
analogue of the nonsteroidal anti-inflammatory drug indoprofen. Both methods, A and B,
were accompanied by the formation of byproducts, which were separated by crystallization.
The investigation of the biological properties for phosphonoindoprofen is in progress.
EXPERIMENTAL
All commercially available reagents were used without further purification. Melting
points are uncorrected. IR spectra were obtained in KBr pellets and were recorded on a
Vertex 70 IR Fourier spectrometer. 1H, 13C, and 31P NMR spectra were measured at 300,
100, and 80 MHz, respectively, for DMSO-d6 solution with TMS as internal or H3PO4
as external standard on Varian VXR-300 and Gemini 2000 (400 MHz) spectrometers.
Chemical shifts (δ) are reported in parts per million. Coupling constants (J) are reported
in Hz. Elemental analyses were performed in the analytical laboratory of this institute. All
solvents were distilled and purified by standard procedures. Compounds 2,12 3,13 and 421
were prepared according to published methods.
Synthesis of Diethyl 1-(4-(Isoindolin-1-one-2-yl)
phenyl)ethylphosphonate (Diethyl Phosphonoindoprofen) (1b)
Method A. A solution of aminophosphonate 2 (131 mg, 0.51 mmol) and methyl
2-brommethylbenzoate 4 (40 mg, 0.17 mmol) in EtOH (5 mL) was refluxed for a 60 h.
After cooling, the reaction mixture was evaporated, dissolved in dichloromethane, washed
with 1N HCl, dried over Na2SO4, and evaporated again. The residue obtained was refluxed
for 5 min with hexane and filtered from insoluble impurities. 1b crystallized upon cooling
as fine colorless needles.
Yield 25 mg (40%); mp 107–108◦C. IR (KBr, cm−1), νmax: 561, 735, 802, 820, 848,
957, 1027, 1096, 1158, 1242, 1308, 1331, 1340, 1386, 1456, 1468, 1517, 1610, 1682,
2872, 2902, 2928, 2978. Anal. calcd. for C20H24NO4P (373.39): C, 64.34; H, 6.48; P, 8.30.
Found: C, 64.38; H, 6.50; P, 8.33. 1H NMR (300 MHz, DMSO-d6), δ: 1.11 (3H, t, J 7.0 Hz,
CH2CH3), 1.22 (3H, t, J 7.0 Hz, CH2CH3), 1.44 (3H, dd, J 18.4, 7.3 Hz, CHCH3), 3.36
(1H, m, CHP), 3.85 (2H, m, OCH2), 3.98 (2H, m, OCH2), 5.03 (2H, s, CH2N), 7.39 (2H,
dd, J 8.6, 2.0 Hz, Ar), 7.55 (1H, m, Ar), 7.67 (2H, m, Ar), 7.79 (1H, d, J 7.5 Hz, Ar), 7.87
(2H, d, J 8.6 Hz, Ar). 13C NMR (100.6 MHz, DMSO-d6), δ: 15.47 (d, J 5.6 Hz), 16.06 (d,
J 5.0 Hz), 16.17 (d, J 5.0 Hz), 36.40 (d, J 139 Hz), 50.32, 61.27 (d, J 5.9 Hz), 61.46 (d,
J 5.9 Hz), 118.89, 122.97, 123.04, 127.91, 128.77 (d, J 6.9 Hz), 131.92, 132.30, 133.83,
137.94, 140.72, 166.30. 31P NMR (80 MHz, DMSO-d6), δ: 31.00.
Method B. A mixture of chloride 3 (0.25 g, 0.92 mmol) and triethylphosphite (1.60
mL, 9.2 mmol) was heated under reflux for a 16 h, cooled, and evaporated. The residue
obtained was refluxed for 5 min with hexane and filtered from insoluble impurities. 1b
crystallized upon cooling as colorless needles.
Yield 109 mg (32%); mp 107–108◦C. Analysis and spectral data were identical to 1b
obtained by method A.

SYNTHESIS OF PHOSPHONOINDOPROFEN
2241
Synthesis of 1-(4-(Isoindolin-1-one-2-yl)phenyl)ethylphosphonic
Acid (1a) (Phosphonoindoprofen)
To a solution of the diethyl phosphonoindoprofen 1b (15 mg, 0.04 mmol) in anhydrous
dichloromethane (5 mL), Me3SiBr (52 µL, 0.4 mmol) was added. The reaction mixture,
after standing overnight, was evaporated. The residue was dissolved in aqueous dioxane
(1:1) (5 mL). After 1 h standing, it was evaporated again and dried. The product was
obtained as a pale solid.
Yield 13 mg (100%); mp 227–228◦C. IR (KBr, cm−1), νmax: 545, 734, 793, 818, 838,
881, 928, 1005, 1038, 1155, 1192, 1251, 1309, 1387, 1448, 1470, 1516, 1610, 1687, 2977.
Anal. calcd. for C16H16NO4P (317.28): C, 60.57; H, 5.08; P, 9.76. Found: C, 60.51; H, 5.10;
P, 9.73. 1H NMR (300 MHz, DMSO-d6), δ: 1.43 (3H, dd, J 17.4, 7.3 Hz, CH3), 3.01 (1H,
dq, J 21.8, 7.3 Hz, CHP), 5.01 (2H, s, CH2N), 7.35 (2H, dd, J 8.6, 2.2 Hz, Ar), 7.55 (1H,
m, Ar), 7.68 (2H, m, Ar), 7.78 (1H, d, J 7.3 Hz, Ar), 7.80 (2H, d, J 8.6 Hz, Ar). 13C NMR
(100.6 MHz, DMSO-d6), δ: 16.15 (d, J 5.0 Hz), 38.46 (d, J 132 Hz), 50.54, 119.20, 123.08,
123.17, 128.02, 128.85 (d, J 6.1 Hz), 131.94, 132.55, 136.32, 137.51, 140.89, 166.35. 31P
NMR (80 MHz, DMSO-d6), δ: 25.80.
REFERENCES
1. Indoprofen. http://en.wikipedia.org/wiki/Indoprofen.
2. M. R. Lunn, D. E. Root, A. M. Martino, S. P. Flaherty, B. P. Kelley, D. D. Coovert, A. H. Burghes,
N. T. Man, G. E. Morris, J. Zhou, E. J. Androphy, C. J. Sumner, and B. R. Stockwell, Chem.
Biol., 11, 1489 (2004).
3. N. Frazin, Pain reliever may provide clues for treating spinal muscular atrophy. US National
Institute of Neurological Disorders and Stroke, March 03, 2005, http://www.ninds.nih.gov/news
and events/news articles/news article SMA indoprofen.htm.
4. K. Samson, Neurology Today, 7(21), 18 (2007).
5. V. V. Nesterov and O. I. Kolodiazhnyi, Synlett, 2400 (2007).
6. A. I. Vovk, I. M. Mischenko, V. Y. Tanchuk, G. A. Kachkovskii, S. Y. Sheiko, O. I. Kolodyazhnyi,
and V. P. Kukhar, Bioorg. Med. Chem. Lett., 18, 4620 (2008).
7. G. O. Kachkovskyi and O. I. Kolodiazhnyi, Phosphorus, Sulfur, and Silicon, 184, 890 (2009).
8. V. P. Kukhar and H. R. Hudson, Eds. Aminophosphonic and Aminophosphinic Acids: Chemistry
and Biological Activity (John Wiley, New York, 2000), Chapters 1, 12–18.
9. O. I. Kolodiazhnyi, Russ. Chem. Rev., 75, 227 (2006).
10. K. W. Jung, K. D. Janda, P. J. Sanfilippo, and M. Wachter, Bioorg. Med. Chem. Lett., 6, 2281
(1996).
11. For synthesis ofα-aryl substituted ethyl phosphonates, see also: N. S. Goulioukina, T. M. Dol-
gina, G. N. Bondarenko, I. P. Beletskaya, N. A. Bondarenko, J.-C. Henry, D. Lavergne, V.
Ratovelomanana-Vidal, and J.-P. Genet, Russ. J. Org. Chem., 38, 573 (2002), and references
therein.
12. F. Kagan, R. D. Birkenmeyer, and R. E. Strube, J. Am. Chem. Soc., 81, 3026 (1959).
13. C. S. N. Prasad, R. Varala, and S. R. Adapa, Heterocycl. Commun., 8, 281 (2002).
14. H. J. Lee, S. J. Lim, S. J. Oh, D. H. Moon, D. J. Kim, J. Taeb, and K. H. Yooa, Bioorg. Med.
Chem. Lett., 18, 1628 (2008).
15. M. H. Norman, D. J. Minick, and G. C. Rigdon, J. Med. Chem., 39, 149 (1996).
16. C. Almansa, L. A. Gomes, F. L. Cavalcanti, R. Rodriguez, E. Carceller, J. Bartroli, J. Garcia-
Rafanell, and J. Forn, J. Med. Chem., 36, 2121 (1993).
17. A. Padwa, D. C. Dean, D. L. Hertzog, W. R. Nadler, and L. Zhi, Tetrahedron, 48, 7565 (1992).
18. J. S. New and J. P. Yevich, J. Heterocycl. Chem., 21, 1355 (1984).

2242
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
19. T. Kametani, K. Kigisawa, M. Hiiragi, H. Ishimaru, S. Hagu, and K. Shirayama, J. Heterocycl.
Chem., 15, 369 (1978).
20. For Arbuzov reaction with sec-alkylhalogenides, see: (a) R. G. Harvey and E. G. LeSombre,
In Topics in Phosphorus Chemistry, vol. 1, M. Grayson and E. J. Griffith, eds. (Interscience,
New York, 1964), p. 58; (b) G. M. Kosolapoff, In Organic Reactions, vol. 6, R. Adams, ed. (John
Wiley & Sons, Inc., New York, 1951), p. 273.
21. D. A. Quagliato, P. M. Andrae, and E. M. Matelan, J. Org. Chem., 65, 5037 (2000).