7,8-Dihydroretinoic Acid Analogues
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1937
of ether. The undissolved solid (TLC, 1 spot, 39% yield) was
recrystallized from acetonitrile: HPLC (1:1 MeCN-1% aque-
ous NH4OAc, 340 nm), 99%; MS m/z 327 (M + H), 296 (M -
OCH3); UV (EtOH) λmax 314 nm (ꢀ 44600); 1H NMR (CDCl3) δ
7.12 (bd, 1H, H10, J 10,11 ) 11.1 Hz), 6.95 (bs, 1H, 7NH), 6.91
(s, 2H, H3′ and H5′), 6.90 (dd, 1H, H11, J 10,11 ) 11.1 Hz, J 11,12
) 15.3 Hz), 6.54 (d, 1H, H12, J 11,12 ) 15.3 Hz), 5.89 (bs, 1H,
H14), 3.73 (s, 3H, OCH3), 2.37 (d, 3H, 13CH3, J 13-CH3,14 ) 1.1
Hz), 2.28 (s, 3H, 4′CH3), 2.20 (s, 6H, 2′CH3 and 6′CH3), 2.18
(bs, 3H, 9CH3). Anal. (C20H25NO3) C, H, N.
was stirred during 1.5 h. A solution of the benzenamine (40
mg, 0.18 mmol) in DMF (3 mL) was added to the acid bromide
(18) solution, and the resulting mixture was stirred at room
temperature during 2 h and at 50 °C during 2 h. The reaction
mixture was poured into water, the aqueous mixture was
extracted with ether, and the ether layer was washed with
brine, dried (MgSO4), and concentrated to an oil that crystal-
lized (yield 38 mg). The solid was triturated with acetonitrile
and then with ether: yield, 28 mg (36%); mp 185-186 °C;
HPLC (7:3 MeCN - 1% aqueous NH4OAc, 340 nm), 100%; MS
m/z 412 (M + H), 396 (M - CH3), 380 (M - OCH3), 356 (M -
Me2C ) CH2); UV (EtOH) λmax, 314 nm (ꢀ 46700); IR (KBr disk,
strong bands, cm-1) 3314, 2956, 1717, 1701, 1649, 1608, 1600,
1497, 1435, 1361, 1280 sh, 1275, 1238, 1225, 1165, 1151, 974;
1H NMR (CDCl3) δ 7.31 (d, 1H, H3′, J 3′,5′ ) 2.1 Hz), 7.16 (d,
1H, H5′, J 3′,5′ ) 2.1 Hz), 7.14 (bd, 1H, H10, J 10,11 ) 11.3 Hz),
Met h yl 7-[(3,5-d im et h oxyp h en yl)a m in oca r b on yl]-3-
m eth yl-2,4,6-octa tr ien oa te (12c) was prepared according to
the procedure outlined for 12a . The reaction mixture was
concentrated in vacuo to a solid that was recrystallized from
ethyl acetate-hexane: yield, 61%; TLC, 1 spot; mp 122-123
°C; MS m/z 346 (M + H); UV (EtOH) λmax 315 nm (ꢀ 40100);
IR (KBr disk, strong bands, cm-1) 3295 (OCH3, broad), 1719,
1645, 1604, 1583, 1552, 1455, 1420, 1292, 1259, 1237, 1204,
7.10 (bs, 1H, NH), 6.91 (dd, 1H, H11, J 10,11 ) 11.3 Hz, J 11,12
)
15.2 Hz), 6.56 (d, 1H, H12, J 11,12 ) 15.2 Hz), 5.89 (bs, 1H, H14),
3.73 (s, 3H, OCH3), 2.38 (d, 3H, 13CH3, J 13-CH3,14 ) 0.9 Hz),
2.20 (bs, 6H, 6′CH3, 9CH3), 1.38 (s, 9H, 2′C(CH3)3), 1.31 (s,
9H, 4′C(CH3)3). Anal. (C26H37NO3‚1/3 H2O) C, H, N.
1
1160, 1152, 1066, 970, 834; H NMR (CDCl3) δ 7.39 (bs, 1H,
7NH), 7.04 (dq, 1H, H10, J 10,11 ) 11.1 Hz, J 10,9-CH3 ) 1.1 Hz),
6.87 (dd, 1H, H11, J 10,11 ) 11.1 Hz, J 11,12 ) 15.0 Hz), 6.83 (d,
2H, H2′, H6′, J 2′,4′ ) J 4′,6′ ) 2.2 Hz), 6.54 (d, 1H, H12, J 11,12
)
7-[(5-Meth oxy-2-m eth ylph en yl)am in ocar bon yl]-3-m eth -
yl-2,4,6-octa tr ien oic Acid (13a ). A solution of 12a (80 mg),
methanol (5 mL), and 1 N sodium hydroxide (3 mL) was boiled
under reflux during 4.5 h and then concentrated in vacuo to a
solid. The residue was dissolved in water, the solution was
extracted with ether, and the aqueous layer was acidified to
pH 3 and extracted with ethyl acetate. The organic layer was
dried (MgSO4) and concentrated to a pale yellow solid [yield,
72 mg (93.5%); HPLC (340 nm), 100%] that was recrystallized
from acetonitrile: mp 191-192 °C; UV (EtOH)24 λmax 312 nm
(ꢀ 43100); IR (KBr disk, strong bands, cm-1) 3360, 3350, 2920,
1697, 1650, 1618, 1601, 1587, 1530, 1491, 1457, 1442, 1418,
1297, 1252, 1239, 1187, 1163, 1036, 966; 1H NMR (Me2SO-d6)
δ 12.3 (bs, 1H, COOH), 9.39 (s, 1H, NH), 7.12 (d, 1H, H3′, J 3′,4′
) 8.4 Hz), 7.05 (dq, 1H, H10, J 10,11 ) 11.3 Hz, J 10,9-CH3 ) 1.1
Hz), 6.97 (dd, 1H, H11, J 10,11 ) 11.3 Hz, J 11,12 ) 14.3 Hz), 6.93
(d, 1H, H6′, J 4′,6′ ) 2.7 Hz), 6.72 (dd, 1H, H4′, J 4′,6′ ) 2.7 Hz,
J 3′,4′ ) 8.4 Hz), 6.68 (d, 1H, H12, J 11,12 ) 14.3 Hz), 5.92 (bs,
1H, H14), 3.71 (s, 3H, 5′OCH3), 2.29 (d, 3H, 13CH3, J 13-CH3,14
15.0 Hz), 6.26 (t, 1H, H4′, J 2′,4′ ) J 4′,6′ ) 2.2 Hz), 5.90 (bs, 1H,
H14), 3.80 (s, 6H, 3′OCH3, 5′OCH3), 3.74 (s, 3H, COOCH3),
2.37 (d, 3H, 13CH3, J 13-CH3,14 ) 1.2 Hz), 2.14 (d, 3H, 9CH3,
J 9-CH3,10 ) 1.1 Hz). Anal. (C19H23NO5) C, H, N.
Meth yl
7-[[2-(1,1-Dim eth yleth yl)p h en yl]a m in oca r -
bon yl]-3-m eth yl-2,4,6-octr ien oa te (12d ). A reaction mixture
prepared, as described for 12a , from 2-(1,1-dimethylethyl)-
benzenamine and 17 was heated under reflux overnight. The
solid obtained from the reaction mixture residue was triturated
with ether and then recrystallized from acetonitrile: HPLC
(7:3 MeCN-1% aqueous NH4OAc, 340 nm), 99.8%; MS m/z
342 (M + H), 326 (M - CH3), 310 (M - OCH3), 193 (M - tert-
butylphenylamino); UV (EtOH) λmax 314 nm (ꢀ 43000); IR (KBr
disk, strong bands, cm-1) 3309, 1712, 1649, 1612, 1599, 1500,
1
1483, 1442, 1390, 1288, 1239, 1160, 970; H NMR (CDCl3) δ
7.76 (dd, 1H, H6′, J 4′,6′ ) 1.7 Hz, J 5′,6′ ) 7.9 Hz), 7.55 (bs, 1H,
NH), 7.41 (dd, 1H, H3′, J 3′,5′ ) 1.7 Hz, J 3′,4′ ) 7.9 Hz), 7.25 (dt,
1H, H5′, J 4′,5′ ) 7.8 Hz, J 5′,6′ ) 7.9 Hz, J 3′,5′ ) 1.7 Hz), 7.17 (dt,
1H, H4′, J 4′,6′ ) 1.7 Hz, J 4′,5′ ) 7.8 Hz, J 3′,4′ ) 7.9 Hz), 7.16 (bd,
1H, H10, J 10,11 ) 11.1 Hz), 6.91 (dd, 1H, H11, J 10,11 ) 11.1 Hz,
J 11,12 ) 15.0 Hz), 6.56 (d, 1H, H12, J 11,12 ) 15.0 Hz), 5.90 (bs,
) 0.7 Hz), 2.11 (s, 3H, 2′CH3), 2.09 (s, 3H, 9CH3). Anal. (C18H21
NO4) C, H, N.
-
3-Met h yl-7-[(2,4,6-t r im et h ylp h en yl)a m in oca r b on yl]-
2,4,6-octr a tr ien oic Acid (13b). A mixture of 12b (125 mg),
methanol (10 mL), and 1 N sodium hydroxide (5 mL) was
heated at 60 °C during 2 h, boiled under reflux during 8 h,
and then concentrated to remove methanol. Additional water
was added to the aqueous residue, and the solution was filtered
and acidified to pH 3. A precipitate was collected, dried, and
recrystallized from acetonitrile: yield, 110 mg (91.6%); mp
248-250 °C dec; HPLC (1:1 MeCN - 1% aq. NH4OAc, 340
nm), 100%; MS m/z 314 (M + H), 179 (M - trimethylphenyl
- NH); UV (EtOH)24 λmax 310 nm (ꢀ 45500); IR (KBr disk,
strong bands) 3266, 2915, 1701, 1639, 1623, 1599, 1585, 1505,
1280, 1258, 1238, 1191, 962; 1H NMR (Me2SO-d6) δ 12.18 (bs,
1H, COOH), 9.17 (s, 1H, NH), 7.04 (d, 1H, H10, J 10,11 ) 11.3
Hz), 6.97 (dd, 1H, H11, J 10,11 ) 11.3 Hz, J 11,12 ) 14.7 Hz), 6.89
(s, 2H, H3′ and H5′), 6.66 (d, 1H, H12, J 11,12 ) 14.7 Hz), 5.91
(s, 1H, H14), 2.30 (d, 3H, 13CH3, J 13-CH3,14 ) 0.9 Hz), 2.23 (s,
1H, H14), 3.74 (s, 3H, OCH3), 2.37 (d, 3H, 13CH3, J 13-CH3,14
)
1.1 Hz), 2.19 (d, 3H, 9CH3, J 9-CH3,10 ) 0.9 Hz), 1.43 (s, 9H,
2′C(CH3)3). Anal. (C21H27NO3‚3/4CH3CN) C, H, N.
Meth yl 7-[[2,4-Bis(1,1-dim eth yleth yl)ph en yl]am in ocar -
bon yl]-3-m eth yl-2,4,6-octa tr ien oa te (12e). 2,4-Bis(1,1-dim-
ethylethyl)benzenamine was prepared as described by Keidel
et al.25 from the corresponding nitrobenzene.26 Compound 12e
was obtained from the benzenamine and 17 as described for
12a except that the reaction mixture was boiled under reflux
during 6.5 h. The solid obtained by concentrating the reaction
mixture in vacuo was triturated with small amounts of
acetonitrile, and the residue (57% yield) was recrystallized
from the same solvent: HPLC (7:3 MeCN-1% aq NH4OAc,
340 nm), 99.5%; UV (EtOH) λmax 314 nm (ꢀ 47000); IR (KBr
disk, strong bands cm-1) 3255 (broad), 2961, 1721, 1648, 1601,
1
1507, 1361, 1290, 1244, 1237, 1162, 963; H NMR (CDCl3) δ
3H, 4′CH3), 2.08 (s, 9H, 2′CH3, 6′-CH3, 9CH3). Anal. (C19H23
-
7.53 (d, 1H, H6′, J 5′,6′ ) 8.2 Hz), 7.46 (bs, 1H, NH), 7.43 (d,
1H, H3′, J 3′,5′ ) 2.2 Hz), 7.27 (dd, 1H, H5′, J 3′,5′ ) 2.2 Hz, J 5′,6′
) 8.2 Hz), 7.15 (bd, 1H, H10, J 10,11 ) 11.4 Hz), 6.90 (dd, 1H,
H11, J 10,11 ) 11.4 Hz, J 11,12 ) 15.0 Hz), 6.55 (d, 1H, H12, J 11,12
) 15.0 Hz), 5.90 (bs, 1H, H14), 3.73 (s, 3H, COOCH3), 2.37 (d,
3H, 13CH3, J 13-CH3,14 ) 1.1 Hz), 2.18 (s, 3H, 9CH3), 1.43 (s,
9H, 2′C(CH3)3), 1.32 (s, 9H, 4′C(CH3)3). Anal. (C25H35NO3) C,
N; H: calcd. 8.87; found 9.28.
NO3) C, H, N.
7-[(3,5-Dim et h oxyp h en yl)a m in oca r b on yl]-3-m et h yl-
2,4,6-octa tr ien oic a cid (13c) was obtained from 12c by a
procedure similar to that described for 13b: yield, 66%; HPLC
(1:1 MeCN-1% aq NH4OAc, 340 nm), 99.8%; UV (EtOH)24 λmax
1
315 nm (ꢀ 40200); MS m/z 332 (M + H); H NMR (Me2SO-d6)
δ 12.22 (bs, 1H, COOH), 9.71 (bs, 1H, NH), 7.00 (d, 2H, H2′,
H6′, J 2′,3′ ) J 3′,6′ ) 2.2 Hz), 6.96 (m, 2H, H10, H11), 6.68 (m,
1H, H12), 6.21 (t, 1H, H4′, J 2′,3′ ) J 4′,6′ ) 2.2 Hz), 5.91 (s, 1H,
H14), 3.71 (s, 6H, 3′OCH3, 5′OCH3), 2.30 (d, 3H, 13CH3,
J 13-CH3,14 ) 1.1 Hz), 2.07 (s, 3H, 9CH3). Anal. (C18H21NO5) C,
H, N.
Meth yl 7-[[2,4-Bis(1,1-d im eth yleth yl)-6-m eth ylp h en yl]-
a m in oca r bon yl]-3-m eth yl-2,4,6-octa tr ien oa te (12f). 2,4-
Bis(1,1-dimethylethyl)-6-methylbenzenamine was prepared as
described by Keidel et al.25 from the corresponding nitroben-
zene.26 Ester-acid 14 (40 mg, 0.19 mmol) was suspended in
benzene (5 mL), phosphorus tribromide (40 mg, 0.15 mmol)
was added, and the mixture was warmed to effect solution and
7-[[2,4-Bis(1,1-d im eth yleth yl)p h en yl]a m in oca r bon yl]-
3-m eth yl-2,4,6-octa tr ien oic a cid (13e) was obtained from