964
H.D. H. Showalter, A. D. Sercel, M. A. Stier and W. R. Turner
Vol. 38
methanol filtrate was concentrated to provide 15.8 g of additional
impure product in two crops. These were combined and
recrystallized from methanol to give 7.2 g (9%) of pure 9, mp
21 hours. The cooled mixture was concentrated to an oily solid
that was dissolved in 150 mL of water. The aqueous solution was
washed with chloroform (2 x 150 mL), then concentrated to leave
an off-white solid. The solid was dissolved in 500 mL of
methanol/concentrated aqueous ammonia (20:1), then
chromatographed over silica gel eluting with the same solvent
mixture. Fractions containing pure product were combined then
concentrated to leave 21 g of a solid, mp 110-111°. The solid was
recrystallized from 400 mL of ethyl acetate to give 19.4 g (79%)
of 3 as the free base, mp 112-113°. The material was dissolved in
183-187°.
3,4-Dihydro-5-methyl-1(2H)-isoquinolinone (2).
A mixture of 50 g (314 mmol) of isoquinolinone 9 in 500 mL
of glacial acetic acid was hydrogenated at 50 psi over 2 g of 20%
palladium on charcoal at 25° until the theoretical amount of
hydrogen had been absorbed. The mixture was filtered and
concentrated to a solid that was crystallized from 220 mL of
3
00 mL of ethanol and 7.2 mL (86.4 mmol) of concentrated
2
-propanol to give 37.2 g (73%) of 2, mp 139-141°, as white
hydrochloric acid was added. The solution was concentrated to a
solid that was recrystallized from a solution of 1.5 L 2-propanol
and 150 mL water to afford 17.9 g (64%) of 3 as the hydro-
plates. The mother liquor was concentrated to afford an
1
additional 10.9 g (22%) of 2 in two crops, mp 139-141°. H NMR
(
(
(
(
deuteriochloroform): δ 7.95 (d, J = 7.4 Hz, 1H), 7.34-7.22
1
chloride salt, mp 259-260°. H NMR (DMSO-d ): δ 9.13 (br s,
6
m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 2.92 (t, J = 6.7 Hz, 2H), 2.32
2H), 7.95 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.8, 1H),
7.18 (d, J = 7.9 Hz, 1H), 4.12 (t, J = 6 Hz, 2H), 3.49 -3.33
(m, 2H), 3.06 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.55 (t, J = 5.4
Hz, 3H), 2.12 (qtp, J = 6.1, 7.3 Hz, 2H); IR (potassium bromide):
-
1
s, 3H); IR (potassium bromide): 1658 cm ; EIMS m/z
+
relative %): 161 (M , 89), 132 (100).
Anal. Calcd. for C H NO: C, 74.51; H, 6.88; N, 8.69. Found:
1
0 11
C, 74.46; H, 6.78; N, 8.62.
-1
+
1
663 cm ; EIMS m/z (relative %): 234 (M , 17), 44 (100).
Anal. Calcd. for C13H18N O •HCl: C, 57.67; H, 7.07; N,
0.35; Cl¯, 13.09. Found: C, 57.30; H, 7.26; N, 9.97; Cl¯, 12.55.
3
,4-Dihydro-5-hydroxy-1(2H)-isoquinolinone (11).
2 2
1
A mixture of 50 g (310 mmol) of 1,5-dihydroxy-1(2H)-
isoquinoline (10) in 1.6 L of glacial acetic acid and 5 g of 20%
palladium on charcoal was hydrogenated at 50° until the
theoretical amount of hydrogen had been absorbed. The solution
REFERENCES AND NOTES
[
1] M. J. Suto, W. R. Turner, C. M. Arundel-Suto, L. M. Werbel
and J. S. Sebolt-Leopold, Anti-Cancer Drug Design, 7, 107 (1991).
2] M. J. Suto, W. R. Turner, and L. M. Werbel, U.S. Patent
177075 (1993); Chem. Abstr. 113:132025y (1990).
3] C. M. Arundel-Suto, S. V. Scavone, W. R. Turner, M. J. Suto
and J. S. Sebolt-Leopold, Radiat. Res., 126, 367 (1991).
4] J. S. Sebolt-Leopold and S. V. Scavone, Int. J. Radiat. Oncol.,
was concentrated to a solid that was crystallized from water
1
(
600 mL) to give 43 g (85%) of 11 [18], mp 195.5-197°. H NMR
[
(
DMSO-d ): δ 9.80 ( s, 1H), 7.83 ( s, 1H), 7.33 ( d, J = 7.3 Hz, 1H),
6
5
7
2
1
.13 ( t, J = 7.8 Hz, 1H), 6.96 ( d, J = 7.9 Hz, 1H), 3.33 (m, 2H),
[
.75 (t, J = 6.7 Hz, 2H); IR (potassium bromide): 3200, 1658,
-1
+
579, 790 cm ; EIMS m/z (relative %): 163 (M , 96), 51 (100).
Anal. Calcd. for C H NO : C, 66.25; H, 5.56; N, 8.58. Found:
[
9
9
2
Biol., Phys. , 22, 619 (1992).
C, 66.62; H, 5.46; N, 8.45.
[5] B. E. Norcross, J. M. Lansinger and R. L. Martin, J. Org.
Chem., 42, 369 (1977).
3,4-Dihydro-5-(3-chloropropoxy)-1(2H)-isoquinolinone (12).
[6] G. Simchen and W. Krämer, Chem. Ber., 102, 3656 (1969).
A mechanically stirred mixture of 40 g (245 mmol) of the
From 20 g of acid 4, 11.3 g (68%) of indanone 5 was obtained by
sublimation.
dihydroisoquinolinone 11, 88 g (637 mmol) of anhydrous
potassium carbonate, and 1 L of absolute ethanol was heated
under nitrogen at reflux. After 1 hour, 121 mL (1.22 mol) of
[
7] Indanone 5 has also been prepared in 83 % yield by
methanesulfonic acid cyclization of 4 on a 5 g scale ; see V. Premasagar,
V. A. Palaniswamy and E. J. Eisenbraun, J. Org. Chem., 46, 2974 (1981).
1
-bromo-3-chloropropane was added dropwise over a 20 minute
It has also been synthesized in 95% yield by AlCl -catalyzed Friedel-
period. The mixture was refluxed for 2 hours, cooled to 60°,
filtered, and the filtrate was concentrated to a white solid. The
solid was dissolved in 375 mL of chloroform, and the solution
was washed with water (3 x 125 mL), dried, and concentrated to
a solid that was triturated in hot ethyl acetate. After cooling, the
3
Crafts reaction of the propionyl chloride (no scale reported); see N. P.
Buu-Hoï, N. Hoán, and N. D. Xuong, J. Chem. Soc., 3499 (1951).
[
[
8] M. Tomita and S. Minami, J. Chem. Soc. (C), 183 (1969).
9] T. Kametani, H. Nemoto, and S. Takano, Chem. Pharm. Bull.,
1
6, 367 (1968).
solid was collected by filtration and dried to give 50.6 g (86%) of
[10] M. W. Fuller, R. H. Quacchia, and J. A. Weigold, J. Chem.
Soc. Perkin Trans. 2, 771 (1992).
1
1
7
6
2
2
1
2, mp 132-134°. H NMR (deuteriochloroform): δ 7.71 (d, J =
.8 Hz, 1H), 7.30 (t,J = 8.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H),
.68 (s, 1H), 4.16 (t,J = 5.8 Hz, 6.4 Hz, 2H), 3.76 (t,J = 6.4 Hz,
H), 3.55 (dt, J = 6.7 Hz, 2.8 Hz, 2.9 Hz, 2H), 2.97 (t, J = 6.7 Hz,
H), 2.28 (q, J = 6.1 Hz, 2H); IR (potassium bromide): 1660,
[11] K. T. Potts and R. Robinson, J. Chem. Soc., 2466 (1955).
[12] B. S. Lee, S. Chu, I. Y. Lee, B.-S. Lee, C. E. Song, D. Y. Chi,
Bull. Korean Chem. Soc. 21, 860 (2000).
[13] F. Eloy and A. Deryckere, Helv. Chem. Acta, 52, 1755 (1969).
[14] F. Eloy and A. Deryckere, Helv. Chim. Acta, 53, 645 (1970).
[15] T. Izumi, Y. Nishimoto, K. Kohei, and A. Kasahara,
-1
+
580 cm ; EIMS m/z (relative %): 253 (M , 22), 91 (100).
Anal. Calcd. for C H ClNO : C, 60.13; H, 5.89; N, 5.84; Cl,
1
2
14
2
J. Heterocyclic Chem., 27, 1419 (1990).
16] J. M. Berry, C. Y. Watson, W. J. D. Whish, and
M. D. Threadgill, J. Chem. Soc., Perkin Trans. 1, 1147 (1997).
17] I. V. Ekhato and C. C. Huang, J. Labelled Compd.
Radiopharm. 34, 627 (1994).
18] Similar conditions are described for reduction of 10 on a 5 g
1
4.79. Found: C, 59.95; H, 5.91; N, 5.80; Cl, 14.72.
[
3
,4-Dihydro-5-[3-(methylamino)propoxy]-1-(2H)-isoquino-
[
linone, Monohydrochloride (3).
A mixture of 25 g (104 mmol) of dihydroisoquinolinone 12,
[
5
00 mL of 40% aqueous methylamine, and 550 mL of methanol
scale; see K. Nakagawa and T. Nishi, Japanese Patent 75106976 (1975);
Chem. Abstr., 84:59233r (1976).
was heated at 80° with stirring in a Parr pressure vessel for