A short synthesis of the PARP inhibitor 2-(4-trifluoro-methylphenyl)benzimidazole-4-carboxamide (NU1077)

Article abstract of DOI:10.1002/jhet.5570380427

A four-step synthesis of the PARP inhibitor 2-(4- trifluoromethylphenyl)benzimidazole-4-carboxamide (1, NU1077) is presented. Condensation of 2,3-diaminotoluene and 4-trifluoromethylbenzaldehyde afforded 4-methyl-2-(4-trifluoromethylphenyl)benzimidazole.

Full text of DOI:10.1002/jhet.5570380427

Jul-Aug 2001
A Short Synthesis of the PARP Inhibitor 2-(4-Trifluoro-
methylphenyl)benzimidazole-4-carboxamide (NU1077)
Steven C. Austen and John M. Kane*
979
Aventis Pharmaceuticals, Inc., 2110 E. Galbraith Road, Cincinnati, Ohio 45215
Received March 15, 2001
A four-step synthesis of the PARP inhibitor 2-(4-trifluoromethylphenyl)benzimidazole-4-carboxamide (1,
NU1077) is presented. Condensation of 2,3-diaminotoluene and 4-trifluoromethylbenzaldehyde afforded 4-
methyl-2-(4-trifluoromethylphenyl)benzimidazole. Oxidation of the methyl group with potassium perman-
ganate in warm t-butanol afforded the carboxylic acid that was converted to the corresponding carboxamide
via the acid chloride.
J. Heterocyclic Chem., 38, 979 (2001).
Poly(ADP-ribose)polymerase (PARP: EC 2.4.2.30) is an
leading to only a 10% yield of methyl 2-(4-trifluoromethyl-
phenyl)benzimidazole-4-carboxylate (4) following cycliza-
tion in acetic acid. A final step completed this seven-step
synthesis in an overall yield of 1%. Not wishing to dupli-
cate this synthesis, we sought an alternative preparation of
1. We now wish to report that 1 may be conveniently pre-
pared in a four-step sequence starting with commercially
available 2,3-diaminotoluene (5) (Scheme 2).
abundant enzyme found in the nuclei of most eukaryotic
cells, where it is thought to play an important physiological
role in the repair of DNA strand breaks [1]. Once activated,
PARP catalyzes the attachment of ADP-ribose units to
nuclear proteins and to itself, in the process consuming four
molecules of ATP for each NAD that is regenerated [2]. In
disease states where an over activation of PARP is
observed, e.g., those involving ischemia-reperfusion, the
+
ensuing massive depletion of NAD and ATP results in
Scheme 2
necrosis [3]. Thus, inhibitors of PARP have been proposed
as agents for the treatment of cerebral [4], myocardial [5],
and renal [6] ischemia. It has also been proposed that
inhibitors of this enzyme may potentiate the effects of can-
cer chemo- and radiotherapy [7]. In this regard, selected 2-
arylbenzimidazole-4-carboxamides have been reported as
potent inhibitors of PARP [7b]. In conjunction with our
own studies in this area, we were asked to prepare 2-(4-
trifluoromethylphenyl)benzimidazole-4-carboxamide (1,
NU1077) as a biological reference standard. The published
synthesis [8] of 1 started with 3-nitrophthalic anhydride (2)
(Scheme 1). The fifth step of the synthesis, the acylation of
methyl 2,3-diaminobenzoate (3), was a particular problem,
Scheme 1
Condensation of 5 and 4-trifluoromethylbenzaldehyde in
the presence of sodium bisulfite afforded the corresponding
benzimidazole 6 in 73% yield [9]. Numerous methods exist
for the oxidation of heteroaromatic methyl groups to car-
boxylic acids. A majority of these oxidations rely on the use
of either nitric acid at elevated temperatures, chromium tri-
oxide in sulfuric acid, selenium dioxide, or potassium per-
manganate. In our case, we had to keep in mind that aro-
matic trifluoromethyl groups have been hydrolyzed to the
corresponding carboxylic acids under both acidic [10] and
alkaline conditions [11]. We also wished to avoid selenium
dioxide for toxicity reasons. Ultimately, we found that the
oxidation of 6 with potassium permanganate in aqueous t-
butanol afforded the desired carboxylic acid 7 in 55% yield
[12]. Carboxylic acid 7 was then converted to the corre-
sponding acid chloride that, without purification, was
treated with ammonium hydroxide to yield 1 in 53% yield.

980
S. C. Austen and J. M. Kane
Vol. 38
Anal. Calcd for C H F N O : C, 58.83; H, 2.96; N, 9.15.
Found: C, 58.72; H, 3.07; N, 9.10.
In conclusion, we have developed a short synthesis of
15
9 3 2 2
the PARP inhibitor 2-(4-trifluoromethylphenyl)benzimida-
zole-4-carboxamide (1, NU1077) that proceeded in an
overall yield of 21%. The synthetic sequence should be
amenable to the preparation of a variety of analogs provid-
2-(4-Trifluoromethylphenyl)benzimidazole-4-carboxamide (1,
NU1077).
Oxalyl chloride (1.0 mL, 11 mmol) was added dropwise to a
stirred suspension of carboxylic acid 7 (1.7 g, 5.6 mmol), dry
dimethylformamide (4 drops) and dry tetrahydrofuran (60 mL).
After stirring at room temperature for 2 hours, the solvent was
evaporated at reduced pressure. The resulting solid was sus-
pended in dry tetrahydrofuran (100 mL) and ammonium hydrox-
ide (2.0 mL, 30 mmol) was added dropwise. After 2 hours, the
solvent was evaporated at reduced pressure. The concentrate was
partitioned between ethyl acetate (800 mL) and water (100 mL).
The layers were separated and the organic layer was washed with
saturated aqueous sodium bicarbonate. After drying over magne-
sium sulfate, the ethyl acetate was evaporated at reduced pres-
sure. The resulting solid was triturated with hot methanol (10
mL). The product was collected by filtration, washed with
methanol, and dried by suction affording 0.90 g (53%) of 1 as a
colorless solid, mp >300 °C; ir (potassium bromide): 3161, 1164,
ing that potential substituents are stable to the KMnO oxi-
dation conditions.
4
EXPERIMENTAL
All reagents and solvents were used as received. Ir spectra
1
were determined using potassium bromide pellets. H nmr spec-
tra were recorded at 300 MHz. Mass spectra were recorded using
EI methods. Flash chromatography was performed as previously
described [13].
4-Methyl-2-(4-trifluoromethylphenyl)benzimidazole (6).
A solution of 4-trifluoromethylbenzaldehyde (14.25 g, 81.84
mmol) in methanol (50 mL) was added dropwise to a stirred mix-
ture of 2,3-diaminotoluene (10.0 g, 81.8 mmol), sodium bisulfite
(9.4 g, 90 mmol), and methanol (100 mL). The reaction was heated
at reflux for 1 hour. After cooling to room temperature, the inor-
ganic material was collected by filtration and rinsed with methanol
(100 mL). The solvent was evaporated at reduced pressure and the
resulting oil was dissolved in ethyl acetate (600 mL). The organic
layer was washed successively with 0.2 M aqueous hydrochloric
acid (2 x 200 mL), saturated aqueous sodium bicarbonate (2 x 200
mL) and saturated aqueous sodium chloride (2 x 200 mL). After
drying over magnesium sulfate, the solvent was evaporated at
reduced pressure. The resulting oil was purified by flash chro-
matography using the step gradient 10% ethyl acetate/hexane, 15%
ethyl acetate/hexane affording 16.6 g (73%) of 6 as an off-white
solid, mp 89-91 °C; ir (potassium bromide): 3117, 1445, 1332,
-1
1
1597, 1327, 1315, 1170, 1115, 1066 cm ; H nmr (dimethylsul-
foxide-d ): δ 13.70 (s, 1H), 9.30 (s,1H), 8.50-7.77 (m, 7H), 7.45-
6
+
7.38 (m, 1H); ms (EI) m/z (rel intensity) 305 (M , 100%).
Anal. Calcd for C H F N O: C, 59.02; H, 3.30; N, 13.77.
15 10
3 3
Found: C, 58.83; H, 3.28; N, 13.57.
Acknowledgement.
The authors would like to thank Dr. Philip Weintraub for helpful
discussions concerning the role of PARP in various disease states.
REFERENCES AND NOTES
[1] M. Satoh, T. Lindahl, Nature, 356, 356 (1992).
[2] N. A., Berger, Radiat. Res., 101, 4 (1985).
[3] D. R. Janero, D. Hreniuk, H. M. Sharif, K. C. Prout, Am. J.
Physiol., 264, 1401 (1993).
[4a] K. Plaschke, J. Kopitz, M. A. Weigand, E. Martin, H. J.
Bardenheuer, Neurosci. Lett., 284, 109 (2000); [b] S. Ducrocq, N.
Benjelloun, M. Plotkine, Y. Ben-Ari, C. Charriaut-Marlangue, J.
Neurochem., 74, 2504 (2000).
[5] E. Szabados, P. Literati-Nagy, B. Farkas, B. Sumegi, Biochem.
Pharmacol., 59, 937 (2000).
-1 1
1321,1160, 1119, 1069, 846 cm ; H nmr (dimethylsulfoxide-d ): δ
6
12.95 (br s, 1H), 8.42 (d, 2H, J = 7.7 Hz), 7.93 (d, 2H, J = 8.0 Hz),
7.48-7.38 (m, 1H), 7.13 (t, 1H, J = 7.7 Hz), 7.03 (d, 1H, J = 7.3 Hz),
2.59 (s, 3H); ms (EI) m/z (rel intensity) 276 (M , 100%).
+
Anal. Calcd for C H F N •1/3H O: C, 63.83; H, 4.17; N,
15 11
3
2
2
9.93. Found: C, 63,84; H, 4.00; N, 9.89.
2-(4-Trifluoromethylphenyl)benzimidazole-4-carboxylic Acid (7).
Benzimidazole 6 (1.8 g, 6.5 mmol) was stirred and warmed to
approximately 50 °C in t-butanol (30 mL). A 50 °C solution of
potassium permanganate (5.4 g, 34 mmol) in water (50 mL) was
added in 5-10 mL portions over 2.5 hours so that the reaction tem-
perature was maintained between 50-55 °C. The reaction was
stirred overnight at approximately 55 °C. After cooling to room
temperature, the precipitate was collected by filtration. The precip-
itate was washed with water (500 mL) that had been warmed to
approximately 80 °C. The filtrate was extracted with ethyl acetate
(3 x 150 mL) before being acidified with concentrated hydrochloric
acid to pH = 2 (test paper). The aqueous layer was extracted with
ethyl acetate (3 x 250 mL). The organic extracts were combined
and dried over magnesium sulfate. The drying agent was removed
by filtration and the filtrate was evaporated at reduced pressure to
yield 1.1 g (55%) of 7 as a colorless solid, mp >300 °C; ir (potas-
sium bromide): 3296, 1671, 1321, 1286, 1260, 1236, 1209, 1189,
[6] P. K. Chatterjee, K. Zacharowski, S. Cuzzocrea, M. Otto, C.
Thiemermann, FASEB J., 14, 641 (2000).
[7a] S. Jung, E. A. Miranda, J. M. de Murcia, C. Niedergang, M.
Delarue, G. E. Schulz, G. M. de Murcia, J. Mol. Bio., 244, 114 (1994); [b] R.
J. Griffin, S. Srinivasan, A. W. White, K. Bowman, A. H. Calvert, N. J.
Curtin, D. R. Newell, B. T. Golding, Pharm. Sci., 2, 43 (1996).
[8] R. J. Griffin, A. H. Calvert, N. J. Curtin, D. R. Newell, B. T.
Golding, WO 97/04771, 13 February 1997; Chem. Abstr., 126, 212151v
(1997).
[9a] J. Wright, D. Downing, T. Heffner, T. Pugsley, R. MacKenzie, L.
Wise, Bioorg. Med. Chem. Lett., 5, 2541 (1995); [b] J. Wright, T. Heffner, T.
Pugsley, R. MacKenzie, L. Wise, Bioorg. Med. Chem. Lett., 5, 2547 (1995).
[10a] R. Church, R. Trust, J. D. Albright, D. W. Powell, J. Org. Chem.,
60, 3750 (1995); [b] H. Gilman, D. Blume, J. Am. Chem. Soc., 65, 2467
(1943).
[11a] G. W. Fischer, J. Heterocyclic. Chem., 30, 1517 (1993); [b] J.
Bornstein, S. A. Leone, W. F. Sullivan, O. F. Bennett, J. Am. Chem. Soc., 79,
1745 (1957).
-1 1
1181, 1149, 1142, 1112, 1068 cm ; H nmr (dimethylsulfoxide-d ):
6
δ 12.7 (br s, 1H), 8.55 (d, 2H, J = 7.5 Hz), 8.02-7.84 (m, 4H), 7.40-
[12] N. J. Leonard, F. Kaz´mierczak, J. Org. Chem., 52, 2933 (1987).
[13] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem., 43, 2923 (1978).
+
7.32 (m, 1H); ms (EI) m/z (rel intensity) 306 (M , 100%).