Nonsteroidal Antiinflammatory Esters and Amides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 2 273
(m, 1H, NH), 7.06-7.71 (m, 6H); MS(CI) m/z 448 (M + 1). Anal.
hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethanol as
a white solid: 150-152 °C; [R]405 ) -17.7° (c ) 1.06, ethanol);
1H NMR (CDCl3) δ 1.28 (s, 3H), 1.70-1.98 (m, 4H), 2.02 (s,
3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.50 (bs, 1H), 2.66 (t, 3H), 3.90
(m, 1H), 4.33 (s, 1H). Anal. (C15H22O3) C, H.
(C28H33NO4) C, H, N.
(S)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R)-
(3,4-Dih ydr o-6-h ydr oxy-2,5,7,8-tetr am eth yl-2H-1-ben zopy-
r a n -2-yl)m eth yl Am id e (5c). Synthesized by method A in
32% yield from (R)-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
2H-1-benzopyran-2-yl)methylamine hydrochloride and 6-meth-
oxy-R-methylnaphthaleneacetic acid: white solid; mp 130-132
°C; [R]D ) -15.5° (c ) 0.526, ethanol); 1H NMR (CDCl3) δ 1.05
(s, 3H), 1.68 (m, 8H), 2.04 (2s, 6H), 2.56 (m, 2H), 3.29 (m, 1H),
3.44 (m, 1H), 3.57 (m, 1H), 3.92 (s, 3H), 4.18 (s, 1H), 5.76 (m,
(R)-2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-tetr a m eth yl-2H-1-
ben zop yr a n -2-yl)eth a n ol. Synthesized by the method de-
scribed for (S)-2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
2H-1-benzopyran-2-yl)ethanol from (R)-(3,4-dihydro-6-hydroxy-
2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)acetic acid43 in 82.5%
yield: white solid; 150-152 °C; [R]405 ) +17.7° (c ) 1.02,
1
ethanol); H NMR (CDCl3) δ 1.28 (s, 3H), 1.70-1.98 (m, 4H),
1H), 7.06-7.71 (m, 6H); MSCI m/z 448 (M + 1). Anal. (C28H33
NO4) C, H, N.
-
2.02 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.50 (bs, 1H), 2.66 (t,
3H), 3.90 (m, 1H), 4.33 (s, 1H). Anal. (C15H22O3) C, H.
(S)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R)-
2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-t et r a m et h yl-2H-1-b en -
zop yr a n -2-yl)eth yl Ester (6b). Synthesized by method A in
48.6% yield from (R)-2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetra-
methyl-2H-1-benzopyran-2-yl)ethanol and 6-methoxy-R-meth-
ylnaphthaleneacetic acid: white solid; mp 120-121 °C; [R]D
) +43.6° (c ) 0.420%, ethanol); 1H NMR (CDCl3) δ 1.17 (s,
3H), 1.56 (d, 3H), 1.65-1.75 (m, 2H), 1.81-1.95 (m, 2H), 2.04
(s, 3H), 2.05 (s, 3H), 2.13 (s, 3H), 2.40-2.55 (m, 2H), 3.84 (q,
1H), 3.91 (s, 3H), 4.17 (s, 1H), 4.20-4.33 (m, 2H), 7.10-7.70
(m, 6H). Anal. (C29H34O5) C, H.
(S)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R,S)-
(6-Acetoxy-3,4-dih ydr o-2,5,7,8-tetr am eth yl-2H-1-ben zopy-
r a n -2-yl)m eth yl Am id e (5d ). Acetyl chloride (0.35 g, 4.46
mmol) was added to a solution of 5a (1.00 g, 2.23 mmol) and
triethylamine (0.91 g, 8.99 mmol) in THF (40 mL) at 0 °C.
The reaction mixture was allowed to warm to ambient tem-
perature and was stirred for 2 h. The reaction mixture was
concentrated in vacuo, and the residue was dissolved in CH2Cl2
(60 mL). The resulting mixture was washed with water (60
mL). The organic layer was separated, dried (MgSO4), and
concentrated in vacuo. The residue was purified by flash
chromatography using 1:9 hexane-EtOAc as an eluent.
Crystallization from a mixture of EtOAc and hexane afforded
0.80 g (73%) of 5d as a white solid: mp 128-130 °C; 1H NMR
(CDCl3) δ 1.05 (d, 3H), 1.61-174 (m, 9H), 2.04 (m, 5H), 2.32
(s, 3H), 2.52 (m, 2H), 3.25-3.51 (m, 2H), 3.71 (q, 1H), 3.91 (s,
3H), 5.73 (m, 1H), 7.11-7.70 (m, 6H); MS(CI) m/z 490 (M +
1). Anal. (C30H35NO5) C, H, N.
(S)-6-Met h oxy-r-m et h yln a p h t h a len ea cet ic Acid , (S)-
2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-t et r a m et h yl-2H-1-b en -
zop yr a n -2-yl)eth yl Ester (6c). Synthesized by method A in
59.4% yield from (S)-2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetra-
methyl-2H-1-benzopyran-2-yl)ethanol and 6-methoxy-R-meth-
ylnaphthaleneacetic acid: white solid; mp 73.5-75 °C; [R]D
)
+20.1° (c ) 0.413%, ethanol); 1H NMR (CDCl3) δ 1.16 (s, 3H),
1.57 (d, 3H), 1.60-1.75 (m, 2H), 1.81-1.93 (m, 2H), 2.05 (s,
6H), 2.14 (s, 3H), 2.46 (t, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.19
(s, 1H), 4.20-4.40 (m, 2H). 7.11-7.70 (m, 6H). Anal. (C29H34O5)
C, H.
(S)-6-Met h oxy-r-m et h yln a p h t h a len ea cet ic Acid , (S)-
(6-Acetoxy-3,4-dih ydr o-2,5,7,8-tetr am eth yl-2H-1-ben zopy-
r a n -2-yl)m eth yl Am id e (5e). Synthesized by the method
used to prepare compound 5d in 66% yield from 5b: mp 122
°C; [R]D ) -29.2° (c ) 0.507, ethanol); MS(CI) m/z 490 (M +
1); 1H NMR (CDCl3) δ 1.05 (s, 3H), 1.53-165 (m, 9H), 1.91 (m,
5H), 2.32 (s, 3H), 2.48 (m, 2H), 3.25-3.35 (m, 2H), 3.71 (q,
(R)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R)-
2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-t et r a m et h yl-2H-1-b en -
zop yr a n -2-yl)eth yl Ester (6d ). Synthesized by method A in
48% yield from (R)-2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetra-
methyl-2H-1-benzopyran-2-yl)ethanol and 6-methoxy-R-meth-
ylnaphthaleneacetic acid: white solid; mp 116-118 °C; [R]D
) -17.0° (c ) 0.405, ethanol); 1H NMR (CDCl3) δ 1.25 (s, 3H),
1.57-1.92 (m, 10H), 2.05-2.13 (m, 6H), 2.46 (dd, 2H), 3.78
(m, 1H), 3.91 (s, 3H), 4.18 (s, OH), 4.23 (m, 2H), 7.11-7.71
(m, 6H). Anal. (C29H34O5) C, H.
(S)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R,
S)-2-(6-Acetoxy-3,4-d ih ydr o-2,5,7,8-tetr a m eth yl-2H-1-ben -
zop yr a n -2-yl)eth yl Ester (6e). Synthesized by the method
used to prepare compound 5d in 91% yield from 6a : white
solid; mp 108-110 °C; 1H NMR (CDCl3) δ 1.15 (s, 3H), 1.45-
1.60 (m, 5H), 1.70-1.90 (m, 5H), 1.95 (s, 3H), 2.07 (s, 3H), 2.25
(s, 3H), 2.40 (m, 2H), 3.81 (q, 1H), 3.85 (s, 3H), 4.21-4.50 (m,
2H), 7.11-7.81 (m, 6H). Anal. (C31H36O6) C, H.
2-(3,4-Dih ydr o-6-m eth oxy-2,5,7,8-tetr am eth yl-2H-1-ben -
zop yr a n -2-yl)eth a n ol. To a stirred solution of tert-butyldi-
methyldisilyl chloride (3.0 g, 20.2 mmol) and imidazole (3.13
g, 46.0 mmol) in DMF was added 2-(3,4-dihydro-6-hydroxy-
2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethanol (4.6 g, 18.4
mmol). The mixture was allowed to stir 3 h and was then
added to ice water (200 mL). The resulting mixture was
extracted with CH2Cl2 (2 × 100 mL). The combined organic
extracts were washed with brine, dried (MgSO4), and concen-
trated in vacuo. The crude residue was purified by flash
chromatography using 1:9 EtOAc-hexane as an eluent to
afford 3.45 g (52%) of 2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetra-
methyl-2H-1-benzopyran-2-yl) (tert-butyldimethylsilyloxy)-
ethane as a brown oil: 1H NMR (CDCl3) δ 0.37 (s, 6H), 0.88
(s, 9H), 1.26 (s, 3H), 1.75-1.81 (m, 4H), 2.10 (s, 6H), 2.15 (s,
3H), 2.61 (t, 2H), 3.81 (q, 2H), 4.25 (bs, 1H).
1H), 3.92 (s, 3H), 5.73 (m, 1H), 7.08-7.65 (6 H). Anal. (C30H35
NO5) C, H, N.
-
(S)-6-Meth oxy-r-m eth yln a p h th a len ea cetic Acid , (R,S)-
2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-t et r a m et h yl-2H-1-ben -
zop yr a n -2-yl)eth yl Ester (6a ). A solution of 1,3-dicyclohex-
ylcarbodiimide (0.89 g, 4.31 mmol) in CH3CN (25 mL) was
added dropwise to a stirring slurry of 6-methoxy-R-methyl-
naphthaleneacetic acid (0.90 g, 3.91 mmol), 2-(3,4-dihydro-6-
hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethanol (0.98
g, 3.91 mmol),42 and 1-hydroxybenzotriazole hydrate (0.59 g,
4.31 mmol) in CH3CN (50 mL). After stirring for 18 h, the
reaction mixture was concentrated. The residue was parti-
tioned between water (30 mL) and CH2Cl2 (30 mL). The layers
were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic extracts were
washed with water (20 mL), dried (MgSO4), and concentrated.
The residue was purified by flash chromatography using 4:1
hexane-EtOAc as an eluent. Recrystallization from a mixture
of EtOAc-hexane afforded 0.60 g (33.1%) of 6a as a white
solid: mp 99.5-101.5 °C; 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.5-
1.6 (m, 3H), 1.6 (m, 2H), 1.9 (m, 2H), 2.0 (s, 6H), 2.1 (s, 3H),
2.4 (t, 2H), 3.8 (q, 2H), 3.9 (s, 3H), 4.1-4.4 (m, 2H), 7.1-7.7
(m, 6H). Anal. (C29H34O5) C, H.
(S)-2-(3,4-Dih yd r o-6-h yd r oxy-2,5,7,8-tetr a m eth yl-2H-1-
ben zop yr a n -2-yl)eth a n ol. A 1 M solution of lithium alumi-
num hydride in THF (30.3 mL, 30.3 mmol) was added dropwise
to a stirring solution of (S)-(3,4-dihydro-6-hydroxy-2,5,7,8-
tetramethyl-2H-1-benzopyran-2-yl)acetic acid43 (4.0 g, 15.1
mmol) in THF (73 mL) cooled by an ice-water bath. After the
addition was complete, the reaction was warmed at reflux for
2 h. The reaction mixture was cooled in an ice water bath,
and water (1.1 mL), 15% aqueous sodium hydroxide (1.1 mL),
and water (3.4 mL) were added sequentially. Et2O (100 mL)
was added, and the suspension was filtered through Celite.
Upon concentration a solid formed which was recrystallized
from Et2O to afford 3.42 g (77.5%) of (S)-2-(3,4-dihydro-6-
A mixture of 2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
2H-1-benzopyran-2-yl)(tert-butyldimethylsilyloxy)ethane (3.45
g, 9.57 mmol), methyl iodide (10.0 g, 70.4 mmol), and K2CO3
(6.61 g, 47.8 mmol) in CH3CN (50 mL) was stirred at ambient