Acyl Glucuronide and Hydroxy Metabolites of Diclofenac
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11 2823
and the brown reaction mixture was washed with brine, dried
over K2CO3, and evaporated to a dark green oil. Chromatog-
raphy, eluting with 5% EtOAc-hexane, afforded the amine
1423 as a pale yellow oil (0.32 g, 59%). 1H NMR (250 MHz,
CDCl3): δ 3.77 (3 H, s, CH3O), 5.77 (1 H, br s, NH), 6.71-6.83
(4 H, 2 d, 2′-, 3′-, 5′- and 6′-Hs), 6.98 (1 H, t, 4-H), and 7.34 (2
H, d, 3- and 5-Hs). MS (EI): 267, 269, and 271 (M+ for 35Cl2,
35Cl37Cl, and 37Cl2, 84, 55, and 10%).
3.76 (3 H, s, OCH3), 3.82 (2 H, s, ArCH2), 6.53 (1 H, d, J ) 8.6
Hz, 3-H), 6.67 (1 H, dd, J ) 8.6 and 2.9 Hz, 4-H), 6.75 (1 H, d,
J ) 2.9 Hz, 6-H), 6.90 (1 H, t, 4′-H), 7.17 (1 H, br s, NH), and
7.30 (2 H, d, 3′-H + 5′-H). MS (CI, NH3): 353, 355, and 357
(M+ for 35Cl2, 35Cl + 37Cl, and 37Cl2, 100, 66, and 11%).
2-[(2′,6′-Dich lor oph en yl)am in o)]-5-h ydr oxyph en yl-N,N-
d im eth yla ceta m id e (21). The methoxyamide 20 was sub-
jected to BBr3-catalyzed de-O-methylation as described for the
preparation of 11. From 20 (0.353 g, 1 mmol) was obtained 21
(0.303 g, 90%); mp 188-191 °C. Found: C, 56.3; H, 4.7; N,
8.2. C16H16Cl2N2O2 requires C, 56.65; H, 4.75; N, 8.3%. 1H NMR
(250 MHz, CD3OD): δ 3.03, 3.52 (6 H, 2 s, 2 × NCH3), 3.87 (2
H, s, ArCH2), 6.41 (1 H, d, J ) 8.6 Hz, 3-H), 6.58 (1 H, dd, J
) 8.6 and 2.9 Hz, 4-H), 6.72 (1 H, d, J ) 2.9 Hz, 6-H), 7.00 (1
H, approximately t, 4′-H), and 7.38 (2 H, d, 3′-H + 5′-H). MS
(CI, NH3): 339, 341, and 343 (MH+ for 35Cl2, 35Cl37Cl, and 37Cl2,
100, 67, and 12%).
2-[(2′,6′-Dich lor op h en yl)a m in o]-5-h yd r oxyp h en yla ce-
tic Acid (3) (5-Hyd r oxyd iclofen a c). A solution of 1 M NaOH
(2.4 mL) was added to a suspension of amide 21 (0.1 g, 0.29
mmol) in EtOH (1 mL) in a Schlenk tube, and after it was
purged with nitrogen, the mixture was heated at 80 °C for 36
h. Workup as described for 2, but with no chromatography now
required, afforded the 5-OH compound 3 (0.071 g, 80%); mp
176-178 °C. Found: C, 53.7; H, 3.5; N, 4.4. C14H11Cl2NO3
requires C, 53.9; H, 3.55; N, 4.5%. 1H NMR [400 MHz, (CD3)2-
CO]: δ 3.80 (2 H, s, ArCH2), 6.46 (1H, d, J ) 8.5 Hz, 3-H),
6.67 (1 H, dd, J ) 8.5 and 2.8 Hz, 4-H), 6.75 (1 H, br s, NH),
6.86 (1 H, d, J ) 2.8 Hz, 6-H), 7.07 (1 H, t, 4′-H), 7.44 (2 H, d,
3′-H + 5′-H), and 8.04 (1 H, br s, OH). MS (CI, NH3): 312,
314, and 316 (MH+ for 35Cl2, 35Cl37Cl, and 37Cl2, 100, 67, and
12%).
N-(Ch lor oacetyl)-2′,6′-(dich lor oph en yl)-4-(m eth oxyph e-
n yl)a m in e (15). Amine 14 (1.32 g, 4.93 mmol) was dissolved
in chloroacetyl chloride (11.7 g, 8.25 mL), and the resulting
solution was heated at 105 °C for 1.5 h, whereupon TLC
indicated complete reaction. Solvent was removed under high
vacuum to afford crude amide 1523 (2.12 g), which was
1
progressed without purification. H NMR (250 MHz, CDCl3):
δ 3.79, 3.82 (2 s, 3 H, CH3O, restricted rotation), 3.97 and 4.17
(2 s, 2H, CH2Cl, restricted rotation), 6.83-6.93 (2 H, m, ArH),
and 7.19-7.57 (5H, m, ArH). MS (CI, NH3): 344, 346, and 348
(MH+ for 35Cl3, 35Cl237Cl, and 35Cl37Cl2, 100, 95, and 31%).
N-(Ch lor oacetyl)-2′,6′-(dich lor oph en yl)-4-(h ydr oxyph e-
n yl)a m in e (16). An intimate mixture of chloroamide 15 (2.12
g, crude product prepared as above) and finely powdered AlCl3
(2.99 g, 22.4 mmol) was stirred and heated under N2 at an
external temperature of 150-155 °C (oil bath). After 0.5 h, a
viscous but sufficiently mobile liquid resulted, and after 1.5
h, reaction appeared complete by TLC; the mixture was cooled
and partitioned between EtOAc and 1 M HCl, and then, the
aqueous layer was extracted again with EtOAc. The combined
organic extracts were evaporated to give a brown oil, which
was subjected to chromatography, eluting with 20% EtOAc in
hexane, then 30%, to give the product 16 as a brown amor-
phous solid (0.35 g, 17%). 1H NMR [250 MHz, (CD3)2CO]: δ
4.05, 4.33 (2 H, 2 s, ClCH2, restricted rotation), 6.80-6.95 (2
H, 2 d, ArH), 7.20 (ca. 0.5 H, d, ArH), 7.40 (ca. 0.5 H, t, ArH),
7.50-7.60 (ca. 3.5 H, m, ArH), 7.67 (ca. 0.5 H, ArH), 8.44, and
8.75 (1 H, 2s, OH). All of the ArH signals are complicated by
restricted rotation. MS (CI, NH3): 330, 332, and 334 (MH+
for 35Cl3, 35Cl237Cl, and 35Cl37Cl2, 100, 96, and 33%).
Allyl r/â-D-Glu cop yr a n u r on a te (23). This compound,
prepared according to the literature procedure,28 was contami-
nated with significant quantities of DBU (20 to 30 mol %)
following chromatography. Dissolution in DCM followed by
cooling to 0 °C afforded a sticky solid, which on filtration,
washing with cold DCM, and drying was suitable for progres-
sion (DBU content now ca. 2%); the material existed mainly
as the R-anomer, although R-/â-ratios were variable with
1-(2′,6′-Dich lor op h en yl)-1,3-d ih yd r o-5-h yd r oxyin d ol-2-
on e (17). The chloramide 16 (0.35 g, 1.06 mmol) was again
mixed with AlCl3 (0.5 g, 3.75 mmol) and heated under N2 in
an oil bath maintained at 200-220 °C for 4 h. Workup and
chromatographic purification (eluting with 30% EtOAc-hex-
ane) as described for 16 afforded the indolone 1723 (0.11 g, 38%)
1
different batches, and the recovery was about 60%. H NMR
(250 MHz, CD3OD, R-anomer): δ 3.44 (1 H, dd, J ) 9.4 and
3.6 Hz, 2-H), 3.55 (1 H, t, 4-H), 3.72 (1 H, t, 3-H), 4.56 (1 H, d,
J ) 9.8 Hz, 5-H), 4.71 (2 H, m, OCH2CHdCH2), 5.16 (1 H, d,
J ) 3.6 Hz, 1-H), 5.26 and 5.39 (2 H, 2 m, OCH2CHdCH2),
and 5.96 (1 H, m, OCH2CHdCH2). About 5% of the â-anomer
was present. δ (inter alia): 3.21 (0.05 H, dd, J ) 9.2 and 7.8
Hz, 2-H), 3.90 (0.05 H, d, J ) 9.8 Hz, 5-H), and 4.52 (0.05 H,
d, J ) 7.8 Hz, 1-H).
1
as a brown amorphous solid. H NMR [250 MHz, (CD3)2CO]:
δ 3.71 (2 H, s, CH2Ar), 6.25 (1 H, d, J ) 8.3 Hz, 7-H), 6.68-
6.71 (1 H, dd, J ) 8.3 and 2.5 Hz, 6-H), 6.94 (1 H, d, J ) 2.5
Hz, 4-H), 7.57 (1 H, dd, 4′-H), 7.67 (2 H, approximately d, 3′-H
+ 5′-H), and 8.19 (1 H, s, OH). MS (CI, NH3): 294, 296, and
298 (MH+ for 35Cl2, 35Cl37Cl, and 37Cl2, 100, 77, and 18%).
Allyl 1-O-[2-[(2′,6′-Dich lor oph en yl)am in o)]ph en ylacetyl]
â-D-Glu cop yr a n u r on a t e (25). To a solution of free acid 1
(301.9 mg, 1.02 mmol) and PPh3 (270 mg, 1.02 mmol) in THF
(4 mL) and DMF (0.5 mL) at -10 °C was added DIAD (200
µL, 1.02 mmol). After 5 min, a solution of allyl glucuronate 23
(120 mg, 0.52 mmol) in THF (1 mL) and DMF (0.25 mL) was
added slowly over 10 min. The solution turned dark orange.
After 1 h at this temperature and when the reaction was
judged to be complete as monitored by TLC, the solvent was
removed under vacuum. The product was purified by chroma-
tography on silica gel, eluting with 5-20% EtOH in DCM.
Product-rich fractions (UV absorbing and anisaldehyde + ve)
were combined and evaporated to give 25 as an R-/â-mixture
(2:5; 25%) and purified by preparative HPLC (Phenomenex
Semi-Prep Zorbax C-18 250 mm × 10 mm, 2 mL/min, aceto-
nitrile 10-60%, 35 min H2O, retention time 27 min). This
yielded the desired product 25, solely as the â-anomer, as an
amorphous solid (47 mg, 18%). 1H NMR [400 MHz, (CD3)2CO]:
δ 3.52 (1 H, m), 3.61 (1 H, m) and 3.70 (1 H, m, 2′-H, 3′-H and
4′-H), 3.96 (2 H, AB qt, ArCH2CO), 4.07 (1 H, d, J ) 9.5 Hz,
5′-H), 4.65 (2 H, m, OCH2CHdCH2), 5.20 (1 H, dd, J ) 10.5
and 1.4 Hz) and 5.36 (1 H, dd, J ) 17.2 and 1.6 Hz, OCH2-
CHdCH2), 5.68 (1 H, d, J ) 8.0 Hz, 1′-H), 5.94 (1 H, m,
OCH2CHdCH2), 6.49 (1 H, d, J ) 8.0 Hz, ArH), 6.78 (1 H, br
s, NH), 6.96 (1 H, t, ArH), 7.16 (2 H, m, ArH), 7.31 (1 H, dd,
(6-Iodo-3-m eth oxy)ph en yl-N,N-dim eth ylacetam ide (19).
3-Methoxyphenylacetic acid was converted to its N,N-di-
methylamide 1824 as described for 9. A solution of the product
(2.20 g, 11.4 mmol) and N-iodosuccinimide (5.90 g, 26.27 mmol)
in acetonitrile (15 mL) was heated at reflux for 12 h, when
the reaction appeared complete by TLC. The final solution was
filtered and evaporated, and then, the residue was redissolved
in ether (50 mL), washed with 10% aqueous Na2S2O3 and
water, and evaporated. Recrystallization from EtOAc-hexane
gave the iodo compound 19 (2.79 g, 80% in two crops); mp 82-
84 °C (lit.26 mp 86-89 °C). 1H NMR (250 MHz, CDCl3): δ 3.01,
3.03 (6 H, 2 s, 2 × NCH3), 3.77 (5 H, 2 s, OCH3 + ArCH2),
6.56 (1 H, dd, J ) 8.7 and 2.9 Hz, 4-H), 6.86 (1 H, d, J ) 2.9
Hz, 2-H), and 7.69 (1 H, d, J ) 8.7 Hz, 6-H).
2-[(2′,6′-Dich lor oph en yl)am in o)]-5-m eth oxyph en yl-N,N-
d im eth yla ceta m id e (20). A mixture of iodo compound 19
(0.785 g, 2.46 mmol), 2,6-dichloroaniline 13 (0.759 g, 4.68
mmol), anhydrous K2CO3 (0.263 g, 1.86 mmol), CuI (0.026 g),
and freshly activated Cu powder38 (0.086 g) was stirred and
heated at reflux in anhydrous toluene (5 mL) for 24 h. Workup
as for 10 afforded the product 20 as a crystalline solid (0.79 g,
91%); mp 102 °C (from EtOAc-hexane). Found: C, 57.7; H,
5.2; N, 7.95%. C17H18Cl2N2O2 requires C, 57.8; H, 5.1; N, 7.9%.
1H NMR (250 MHz, CDCl3): δ 3.00, 3.19 (6 H, 2 s, 2 × NCH3),