Retinoic Acid Metabolism Blocking Agents
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6725
n-hexane-isopropyl alcohol (95:5, v/v) at a flow rate of 0.75
mL/min, using a photodiode array (PDA) detector. The reten-
tion times for the first (A) and second (B) peaks were 25.19
and 28.89 min, respectively. Eluents of each peak were
carefully collected manually. The fractions were checked for
enantiomeric purity, using conditions essentially similar to
those described above, but with a flow rate of 1.5 mL/min, with
retention times of peaks A and B of 18.42 and 21.42 min,
respectively. The pure fractions for each peak were combined
and evaporated to dryness under vacuum to give 12 mg of peak
A and 16 mg of peak B. The chemical structures were
confirmed by 1H NMR spectrum and identical as expected.
Optical rotations were measured at the sodium line using a
Perkin-Elmer 141 polarimeter and are averages of seven
are provided below. 13C NMR (150 MHz, CDCl3 + DMSO-d6):
δ 167.4 (C-15), 152.6 (C-13), 151.9 (C-31), 142.5 (C-51), 146.0
(C-9), 139.2 (C-8), 138.4 (C-6), 136.3 (C-12), 131.1 (C-11), 130.5
(C-10), 126.4 (C-7), 123.6 (C-5), 118.5 (C-14), 61.1 (C-4), 34.8
(C-2), 34.0 (C-1), 29.1 and 28.2 (C-16 and C-17), 26.3 (C-18),
19.0 (C-3), 13.8 (C-20), and 12.9 (C-19).
4-(()-(1H-1,2,4-Triazol-4-yl)-(E)-retinoic Acid (10). The
method followed that described for 6 but used 8 (250 mg, 0.656
mmol). Trituration in petroleum ether gave pure 10 (193 mg,
80%). Details of most physical and spectroscopic data have
been previously reported.28 Hitherto unreported 13C NMR data
are provided below. 13C NMR (150 MHz, CDCl3 + DMSO-d6):
δ 168.4 (C-15), 152.5 (C-13), 146.5 (C-9), 142.3 (C-21 and C-31),
139.6 (C-8), 137.5 (C-6), 136.5 (C-12), 131.4 (C-11), 130.4 (C-
10), 125.9 (C-7), 123.1 (C-5), 118.9 (C-14), 57.0 (C-4), 34.7 (C-
2), 33.8 (C-1), 29.2 and 28.2 (C-16 and C-17), 27.5 (C-18), 19.1
(C-3), 13.8 (C-20), and 12.9 (C-19).
values. For peak A, (4R)-(-)-5, [R]24 ) - 25.8° (c ) 0.46,
D
CHCl3), and for peak B, (4S)-(+)-5, [R]24D ) + 25.3° (c ) 0.46,
CHCl3), respectively.
4-(()-(1H-Imidazol-1-yl)-(E)-retinoic Acid (6). To a solu-
tion of 5 (2.5 g, 6.57 mmol) in methanol (25 mL) was added 2
N KOH (40 mL, solution in MeOH/H2O, 9:1, v/v), and the
mixture was stirred under an Ar atmosphere at reflux for 2
h, then concentrated to 1/5 the original volume, cooled, poured
into cold water, neutralized (to pH ∼ 7) with 6 N HCl, and
extracted with 5% MeOH in EtOAc (50 mL × 3). The combined
extract was washed with brine (×3), dried (Na2SO4), and
concentrated. Trituration in petroleum ether gave pure 6 (2.2
g, 91%). Details of most physical and spectroscopic data have
been previously reported.28 Hitherto unreported 13C NMR data
are provided below. 13C NMR (150 MHz, CDCl3 + DMSO-d6):
δ 170.1 (C-15), 155.2 (C-13), 147.5 (C-9), 141.7 (C-8), 141.1 (C-
6), 139.4 (C-21), 138.7 (C-12), 133.6 (C-11), 133.2 (C-10), 131.7
(C-7), 129.3 (C-5), 121.3 (C-14), 127.6 (C-41), 120.8 (C-51), 60.7
(C-4), 37.3 (C-2), 37.2 (C-1), 31.6 and 30.8 (C-16 and C-17),
30.4 (C-18), 21.5 (C-3), 16.4 (C-20), and 15.5 (C-19).
4-(()-(1H-1,2,4-Triazol-1-yl)-(E)-methylretinoate (7) and
4-(()-(4H-1,2,4-Triazol-4-yl)-(E)-methylretinoate (8).47 To
a solution of 4 (1.0 gm, 3.0285 mmol) in dry CH3CN (15 mL)
was added 1,1′-carbonyldi(1,2,4-triazole) (CDT) (693 mg, 4.22
mmol), and the reaction mixture was stirred at room temper-
ature for 30 min, was poured into cold water (50 mL), and then
was extracted with 10% MeOH in EtOAc (50 mL × 3). The
combined extract was washed with brine (×2), dried, and
evaporated to give a yellow viscous oil, which was purified by
FCC [silica gel, CH2Cl2/EtOH, (35:1, v/v)] to give first 7 (705
mg, 61.1%): mp 105-108 °C. NMR (300 MHz, CDCl3): δ 1.10
(s, 3H, 16-CH3), 1.13 (s, 3H, 17-CH3), 1.63 (s, 3H, 18-CH3), 2.02
(s, 3H, 19-CH3), 2.36 (s, 3H, 20-CH3), 3.72 (s, 3H, 15-OCH3),
4.82 (s, 1H, 4-H), 5.80 (s, 1H, 14-H), 6.30 (m, 4H, 7-, 8-, 10-
and 12-Hs), 6.99 (t, 1H, J ) 14.7 Hz, 11-H), 7.99 (s, 1H, 31-H),
8.02 (s, 1H, 51-H). 13C NMR (150 MHz, CDCl3): δ 167.4 (C-
15), 152.6 (C-13), 151.9 (C-31), 142.5 (C-51), 146.0 (C-9), 139.2
(C-8), 138.4 (C-6), 136.3 (C-12), 131.1 (C-11), 130.5 (C-10),
126.4 (C-7), 123.6 (C-5), 118.5 (C-14), 61.1 (C-4), 51.0 (15-
OCH3), 34.8 (C-2), 34.0 (C-1), 29.1 and 28.2 (C-16 and C-17),
26.3 (C-18), 19.0 (C-3), 13.8 (C-20), and 12.9 (C-19). HRMS:
calcd 381.2416 (C23H31O2N3), found 381.2442.
4-(()-(1H-Imidazol-1-yl)-N-(imidazolyl)-(E)-retin-
amide (11). To a suspension of 6 (800 mg, 2.18 mmol) in dry
CH3CN (20 mL) was added CDI (460.6 mg, 2.84 mmol), and
the mixture was stirred at room temperature for 1 h, poured
into cold water (100 mL), and then extracted with 5% MeOH
in ether (50 mL × 3). The combined extract was washed with
brine, dried (Na2SO4), and concentrated to give an oily dark
red product. This crude product was dissolved in a mixture of
CH2Cl2/MeOH/Et3N (15:1:0.2, v/v/v) and filtered through a 3
in. silica gel column that was eluted with the same solvent
mixture. The fraction that contained pure 11 (as determined
by TLC) was concentrated, dried under vacuum, and stored
at -20 °C for approximately 12 h to give the desired 11 (850
1
mg, 95%): mp 82-85 °C. H NMR (500 MHz, CDCl3): δ 1.15
(s, 3H, 16-CH3), 1.18 (s, 3H, 17-CH3), 1.65 (s, 3H, 18-CH3), 2.11
(s, 3H, 19-CH3), 2.55 (s, 3H, 20-CH3), 4.59 (t, 1H, J ) 5 Hz,
4-H), 6.26 (d, 1H, J ) 26.5 Hz, 8-H), 6.28 (s, 1H, 14-H), 6.46
(m, 3H, 7-, 10-H and 12-Hs), 6.96 (s, 1H, 41-H), 7.12 (s, 1H,
51-H), 7.14 (s, 1H, 411-H), 7.25 (dd, 1H, J1 )J2 ) 11 Hz, 11-H),
7.55 (s, 1H, 21-H), 7.58 (s, 1H, 511-H), 8.24 (s, 1H, 211-H). 13C
NMR (125 MHz, CDCl3): δ 162.0 (C-15), 159.0 (C-13), 145.1
(C-9), 141.0 (C-21), 139.1 (C-8), 136.9 (C-6 and C-21), 136.3 (C-
12 and C-211), 135.4 (C-10), 133.8 (C-11), 130.7 (C-7), 131.0
(C-5), 129.1 (C-41), 118.5 (C-14), 116.5 (C-511), 115.9 (C-51), 58.4
(C-4), 34.8 (C-2), 29.3 (C-1), 28.3 (C-17), 28.0 (C- 16), 22.8 (C-
18), 19.1 (C-3), 15.3 (C-20), and 13.3 (C-19). HRMS: calcd
416.2576 (C26H32ON4), found 416.2354.
4-(()-(1H-Imidazol-1-yl)-N-(4-hydroxyphenyl)-(E)-reti-
namide (12). Compound 6 (740 mg, 2.02 mmol), p-aminophe-
nol (264.6 mg, 2.424 mmol), and 1-hydroxybenzotriazole
(HOBT) (327.6 mg, 2.424 mmol) were dissolved in dry DMF
(5 mL) and cooled to 0 °C. Dicyclohexylcarbodiimide (DCC),
(500.2 mg, 2.424 mmol) was added, and the mixture was
allowed to warm to room temperature. After stirring for
approximately 20 h, the precipitated dicyclohexyl urea was
filtered off and washed with 5% MeOH in EtOAc. The filtrate
was washed with water, brine, dried (Na2SO4), and concen-
trated to give crude product (1.2 g), which was purified by FCC
(silica gel, CH2Cl2/MeOH/Et3N, 15:1:0.2, v/v/v) to give 12 (510
mg, 55%): mp 125-129 °C. 1H NMR (500 MHz, CDCl3): δ 1.09
(s, 3H, 16-CH3), 1.10 (s, 3H, 17-CH3), 1.59 (s, 3H, 18-CH3), 1.99
(s, 3H, 19-CH3), 2.38 (s, 3H, 20-CH3), 4.53 (t, 1H, J ) 5 Hz,
4-H), 5.89 (s, 1H, 14-H), 6.20 (m, 4H, 7-, 8-, 10-H and 12-Hs),
6.81 (d, 2H, J ) 9 Hz, aromatic Hs), 6.90 (dd, 1H, J1 )J2 ) 11
Hz, 11-H), 6.93 (s, 1H, 41-H), 7.09 (s, 1H, 51-H), 7.37 (d, 2H, J
) 8.5 Hz, aromatic Hs), 7.54 (s, 1H, 21-H), 7.80 (s, 1H, NH).
13C NMR (150 MHz, CDCl3): δ 165.2 (C-15), 154.0 (C-13), 149.3
(C-9), 145.4 (C-111 and 411), 139.5 (C-8), 137.7 (C-6), 137.6 (C-
21), 136.9 (C-12), 134.4 (C-11), 131.4 (C-10), 130.4 (C-7), 126.1
(C-5), 126.1 (C-41), 124.5 (C-51), 122.0 (2 aromatic Cs), 115.9
(2 aromatic Cs), 118.6 (C-14), 58.5 (C-4), 34.7 (C-2), 34.6 (C-
1), 29.2 and 28.2 (C-16 and C-17), 27.8 (C-18), 19.0 (C-3), 12.9
(C-20), and 13.7 (C-19). HRMS: calcd 457.2729 (C29H35O2N3),
found 457.2634.
Further elution with CH2Cl2/EtOH, 20:1, v/v, afforded 8 (390
mg, 33.8%): mp 62-65 °C. NMR (300 MHz, CDCl3): δ 1.10
(s, 3H, 16-CH3), 1.13 (s, 3H, 17-CH3), 1.64 (s, 3H, 18-CH3), 2.02
(s, 3H, 19-CH3), 2.36 (s, 3H, 20-CH3), 3.72 (s, 3H, 15-OCH3),
4.64 (s, 1H, 4-H), 5.81 (s, 1H, 14-H), 6.25 (m, 4H, 7-, 8-, 10-
and 12-Hs), 6.98 (t, 1H, J ) 14.7 Hz, 11-H), 8.15 (s, 1H, 31-
and 51-H). 13C NMR (150 MHz, CDCl3): δ 167.4(C-15), 152.5
(C-13), 146.5 (C-9), 142.3 (C-21 and C-31), 139.6 (C-8), 137.5
(C-6), 136.5 (C-12), 131.4 (C-11), 130.4 (C-10), 125.9 (C-7),
123.1 (C-5), 118.9 (C-14), 57.0 (C-4), 51.0 (15-OCH3), 34.7 (C-
2), 33.8 (C-1), 29.2 and 28.2 (C-16 and C-17), 27.5 (C-18), 19.1
(C-3), 13.8 (C-20), and 12.9 (C-19). HRMS: calcd 381.2416
(C23H31O2N3), found 381.2423.
4-(()-(1H-1,2,4-Triazol-1-yl)-(E)-retinoic Acid (9). The
method followed that described for 6 but used 7 (500 mg, 1.31
mmol). Trituration in petroleum ether gave pure 9 (409 mg,
85%). Details of most physical and spectroscopic data have
been previously reported.28 Hitherto unreported 13C NMR data
4-Hydroxyimino-(E)-methylretinoate (15). A solution of
ketone 3 (400 mg, 1.2192 mmol) in ethanol (8 mL) was treated
with a solution of hydroxylamine hydrochloride (184 mg, 2.65