2840
M. Stockley et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2837–2841
M.S. We also thank Dr. A. Okuyama, Banyu Tsu-
kuba Research Institute, Tsukuba, Japan for helpful
information.
medium pressure chromatography on silica (eluting with an
ethyl acetate/petrol gradient) to give 6 (13.6 g, 57 mmol, 79%)
as a colourless oil. Found C, 59.94; H, 7.17; N, 5.85%.
C12H17NO4 requires C, 60.24; H, 7.16; N, 5.85%; dH
(200 MHz, DMSO-d6) 3.16 (3H, s, NCH3); 3.60 and 3.77 (6H,
2ꢂs, 2ꢂOCH3); 4.21 (2H, s, COCH2); 4.57 (2H, s, ArCH2);
6.85 (2H, d, Ar H-3,5); 7.28 (2H, d, Ar H-2,6). MS (EI) m/z
239 (M+). To a solution of 4-picoline (10.8 g, 11.0 mL,
0.11 mol) in THF (120 mL) under nitrogen at À78 ꢀC was
added dropwise 2.5 M butyllithium in hexanes (40 mL,
0.10 mol). The solution was allowed to warm up to À10 ꢀC,
stirred at this temperature for 15 min and cooled to À78 ꢀC.
After addition of 6 (10.0 g, 41.8 mmol) in THF (40 ml), the
mixture was warmed to 0 ꢀC, stirred for 4 h and finally quen-
ched with 2 M hydrochloric acid. The resulting solution was
washed with ether (120 mL), cooled to 0 ꢀC, and the pH was
adjusted to 8 by addition of saturated aqueous NaHCO3. The
aqueous mixture was extracted with dichloromethane
(3ꢂ250 mL) and the combined extracts were dried (Na2SO4)
and concentrated in vacuo. The crude product was purified by
medium pressure chromatography on silica (eluting with an
ethyl acetate/petrol gradient) to give 7 (8.6 g, 31.7 mmol, 76%)
as a yellow oil. dH (200 MHz, CDCl3) 3.72 (2H, s, CH2); 3.74
(3H, s, OCH3); 4.01 (2H, s, CH2); 4.44 (2H, s, CH2); 6.82 (2H,
d, J=8.4 Hz, Ar H-3,5); 7.05 (2H, d, J=5.8 Hz, pyridyl H-
3,5); 7.18 (2H, d, J=8.4 Hz, Ar H-2,6); 8.47 (2H, d, J=5.8 Hz,
pyridyl H-2,6). A solution of 7 (7.9 g, 29 mmol) in DMF
(20 ml) was treated with dimethylformamide dimethylacetal
(8.7 g, 9.7 mL, 73 mmol), under nitrogen, and heated at 70 ꢀC
for 5 h. The resulting mixture was concentrated in vacuo
(4.3ꢂ10À3 Torr and <50 ꢀC) to give crude 8 that was used
directly without further purification. A solution of 8 in DMF
(25 mL) was added, with stirring under nitrogen, to sodium
methoxide (3.4 g, 63 mmol) and 2-cyanoacetamide (2.7 g,
32 mmol) in DMF (20 mL). The mixture was heated at 95 ꢀC
for 3 h and concentrated in vacuo (3.8ꢂ10À3 Torr and <50 ꢀC).
To the oily residue was added dichloromethane (150 mL) and
water (50 mL), followed by 2 M hydrochloric acid until the pH
of the aqueous solution was 7. The dichloromethane was
separated and the aqueous layer was extracted with dichloro-
methane (4ꢂ120 mL). The combined extracts were dried
(Na2SO4) and evaporated in vacuo. The crude product was
purified by medium pressure chromatography on silica (elut-
ing with a methanol/dichloromethane gradient). The solid
product was recrystallised from ethyl acetate to give 9 (4.69 g,
13.5 mmol, 46%) as yellow crystals, mp 141–142 ꢀC. Found:
C, 69.13; H, 4.66; N, 12.01%. C20H17N3O3 requires C, 69.15;
H, 4.93; N, 12.10%; dH (200 MHz., DMSO-d6) 3.84 (3H, s,
OCH3); 4.40 (2H, s, OCH2Ar); 4.49 (2H, s, CH2OCH2Ar);
6.97 (2H, d, Ar H-3,5); 7.28 (2H, d, Ar H-2,6); 7.50 (2H, d,
pyridyl H-3,5); 8.38 (1H, s, pyridone H-4); 8.69 (2H, d, pyridyl
H-2,6); 13.06 (1H, s, NH). MS (EI) m/z 347 (M+).
References and Notes
1. Smith, G. C. M.; Jackson, S. P. Genes Dev. 1999, 13, 916.
2. Jackson, S. P. Cancer Surveys 1996, 28, 261.
3. Boulton, S.; Kyle, S.; Yalcintepe, L.; Durkacz, B. W. Car-
cinogenesis 1997, 17, 2285.
4. Rosenzweig, K. E.; Youmell, M. B.; Palayoor, S. T.; Price,
B. D. Clin. Cancer Res. 1997, 3, 1149.
5. Boulton, S.; Kyle, S.; Durkacz, B. W. Carcinogenesis 1999,
20, 199.
6. Muller, C.; Calsou, P.; Salles, B. Proc. Amer. Assoc. Cancer
Res. 1999, 38, 522.
7. Wymann, M. P.; Bulgarelli-leva, G.; Zlevebil, M. J.; Pirola,
L.; Vanhaesebroeck, B.; Waterfield, M. D.; Panayotuo, G.
Mol. Cell Biol. 1996, 16, 1722.
8. Izzard, R. A.; Jackson, S. P.; Smith, G. C. M. Cancer Res.
1999, 59, 2581.
9. Sarkaria, J. N.; Tibbetts, R. S.; Busby, E. C.; Kennedy,
A. P.; Hill, D. E.; Abraham, R. T. Cancer Res. 1998, 58, 4375.
10. Banin, S.; Moyal, L.; Sheih, S. Y.; Taya, Y.; Anderson,
C. W.; Chessa, L.; Smorodinsky, N. I.; Prives, C.; Reiss, Y.;
Shiloh, Y.; Ziv, Y. Science 1998, 281, 1674.
11. Take, Y.; Kumano, M.; Hamano Teraoka, H. Y.;
Fukatsu, H.; Nishimura, S.; Okuyama, A. Biochem. Biophys.
Res. Comm. 1995, 215, 41.
12. Take, Y.; Kumano, M.; Teraoka, H.; Nishimura, S.;
Okuyama, A. Biochem. Biophys. Res. Comm. 1996, 221, 207.
13. Banyu Pharmaceutical Co., Ltd Jpn. Kokai Tokkyo Koho
JP 60 97,959, 1985; Chem Abstr. 1985, 103, 123370y
14. Singh, B. Heterocycles, 1985, 23, 1479
15. Robertson, D. W.; Beedle, E. E.; Swartzendruber, J. K.;
Jones, N. D.; Elzey, T. K.; Kauffman, R. F.; Wilson, H.;
Hayes, J. S. J. Med. Chem. 1986, 29, 635.
16. Nahm, S.; Weinreb, S. Tetrahedron Lett. 1981, 22, 3815.
17. To a solution of bromoacetic acid (13.8 g, 0.10 mol) and 4-
methoxybenzyl alcohol (13.8 g, 12.5 ml, 0.10 mol) in THF
(180 mL) under nitrogen at 0 ꢀC, was added sodium hydride
(5.4 g, 0.24 mol) portionwise. The suspension was heated at
reflux for 24 h and quenched with methanol. The mixture was
concentrated in vacuo and the residue was partitioned between
ether (70 mL) and water (70 mL). The ether layer was sepa-
rated and washed with water (70 mL). The combined aqueous
extracts were acidified to pH 4 with hydrochloric acid and the
resulting solution was extracted with dichloromethane
(3ꢂ150 mL). The combined extracts were dried (Na2SO4) and
concentrated in vacuo. The oily residue was crystallised under
cold ether. The white crystals were collected and dried to pro-
vide 5 (17.6 g, 0.09 mol, 94%), dH (200 MHz, CDCl3) 3.79 (3H,
s, OCH3); 4.08 (2H, s, ArCH2); 4.56 (2H, s, COCH2); 6.87
(2H, d, Ar H-3,5); 7.26 (2H, d, Ar H-2,6). MS (EI) m/z=196
(M+). A solution of 5 (14.1 g, 72 mmol) in ethyl acetate (200
ml) was treated with N,O-dimethylhydroxylamine hydrochlo-
ride (7.20 g, 74 mmol), followed by 1,3-dicyclohexyl-
carbodiimide (15.7 g, 76 mmol). The stirred suspension was
treated with triethylamine (8.05 g, 11.1 ml, 80 mmol) at 0 ꢀC
and the resulting mixture was maintained at room temperature
for 16 h. The suspended solid was filtered off and washed with
ethyl acetate. The filtrate was concentrated in vacuo to a
volume of ca. 150 mL. The resulting solution was washed with
ice-cold 1 M hydrochloric acid (2ꢂ100 mL), saturated aqueous
NaHCO3 (2ꢂ100 mL) and brine (100 mL), dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by
18. A solution of 9 (1.00 g, 2.9 mmol) in trifluoroacetic acid
(5 mL) was stirred for 2 h under nitrogen at 0 ꢀC. After con-
centration of the resulting solution in vacuo, the crude product
was triturated with anhydrous ethanol. The solid product was
collected by filtration and dried to give 10 (0.97 g, 2.8 mmol,
98%) as a beige powder, mp ꢃ140 ꢀC (decomp). IR (KBr)
nmax 3225; 3065; 2214 (cyano); 1628 (pyridone); 1497; 1566;
1127 cmÀ1; dH (200 MHz., DMSO-d6) 4.55 (2H, s, CH2); 7.98
(2H, d, J=5.2 Hz., pyridyl H-3,5); 8.48 (1H, s, pyridone H-4);
8.94 (2H, d, J=5.2 Hz, pyridyl H-2,6); 12.79 (1H, s, NH). A
solution of 10 (0.80 g, 2.5 mmol) in DMF (10 mL) was stirred
with activated manganese dioxide (3.0 g) for 2 h under nitro-
gen. The resulting mixture was filtered three times through
Celite, washing well with methanol each time, and the com-
bined filtrates were concentrated in vacuo to provide 11 as a
crude oil. A solution of hydrazine hydrate (3.09 g, 3.0 mL,
52 mmol) in methanol (10 mL) was added to a suspension of