Elagolix, Nonpeptide Antagonist of GnRH Receptor
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7483
1H), 2.95 (m, 1H), 3.60 and 3.65 (s, 3H), 3.86 and 3.87 (s, 3H),
4.15 (m, 1H), 4.38 (m, 0.5H), 4.60-4.80 (m, 1.5H), 5.22 and 5.26
(d, J ) 17.1 Hz, 1H), 5.64 and 5.67 (d, J ) 17.1 Hz, 1H), 6.81-7.00
(m, 2H), 7.11 (t, J ) 5.8 Hz, 1H), 7.18-7.31 (m, 2H), 7.36-7.50
(m, 5H), 7.52 (d, J ) 7.8 Hz, 1H). MS: 646 (MH+). Anal.
(C33H32F5N3O5): C, H, N.
7.8 Hz, 1H), 7.23-7.41 (m, 6H). MS: 582 (MH+). Anal.
(C31H30F3N3O5): C, H, N.
(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluo-
romethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-
1-yl]-1-phenylethylamino}butyric Acid Sodium Salt (10b). To
a solution of methyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-
fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-
2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (7, 63 mg, 0.1
mmol) in 2.4 mL/0.6 mL of MeOH//water was added LiOH (30
mg, 1.25 mmol). The resulting mixture was heated at 45 °C
overnight and concentrated in Vacuo. The crude product was purified
on a LC-MS system to give the acid as a white foam.
(R)-2-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluo-
romethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-
1-yl]-1-phenylethylamino}acetic Acid Trifluoroacetate (8). A
mixture of 3-[(2R)-amino-2-phenylethyl]-5-(2-fluoro-3-methox-
yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-
pyrimidinedione (4b, 120 mg, 0.22 mmol), tert-butyl bromoacetate
(51.5 mg, 0.264 mmol) and triethylamine (22 mg, 31 uL, 0.22
mmol) in acetonitrile (5 mL) was heated to reflux for 16 h. This
solution was cooled to rt and concentrated in Vacuo. The crude
product was purified by chromatography using 4:6 EtOAc/hexane
to give tert-butyl (R)-2-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-
fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-
2H-pyrimidin-1-yl]-1-phenylethylamino}acetate (50 mg, 35%) as
an oil.
The above product was dissolved in a mixture of trifluoroacetic
acid (2 mL) and dichloromethane (2 mL), and the solution was
stirred at rt for 2 h and concentrated in Vacuo to give the title
compound (40 mg) as a white powder. HPLC purity: 100% (220
and 254 nm). 1H NMR (CDCl3): 1.99 (s, 3H), 3.29 and 3.56 (d, J
) 13.8 Hz, 1H), 3.78 and 3.81 (s, 3H), 4.17 and 4.38 (d, J ) 13.8
Hz, 1H), 4.72 (m, 2H), 4.94 (m, 1H), 5.23 and 5.26 (d, J ) 16.8
Hz, 1H), 5.52 and 5.62 (d, J ) 16.8 Hz, 1H), 6.75 (m, 1H), 6.90
(t, J ) 8.2 Hz, 1H), 7.03 (m, 1H), 7.38-7.60 (m, 2H), 7.38 (m,
5H), 7.51 (m, 1H). MS: 604 (MH+). Anal. (C30H26F5N3O5 ·
1.3CF3COOH): C, H, N.
The sodium salt of 10b was synthesized using the following
procedure.
To a solution of ethyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-
3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-di-
hydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (2.6 g, 4.0
mmol) in 30 mL/30 mL of THF/water was added NaOH (1.6 g, 40
mmol). The resulting mixture was heated at 50 °C overnight and
concentrated in Vacuo. The residual aqueous solution was acidified
with 10% citric acid to pH about 3. The product was extracted
with EtOAc, and the organic phase was separated and concentrated
in Vacuo to give a white gel (1.96 g). This acid was passed through
a Dowex MSC-1 macroporous strong cation-exchange column, and
the resulting aqueous solution was lypholized to give the sodium
salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100%
(220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H),
2.16 (t, J ) 6.9 Hz, 2H), 2.50 (t, J ) 6.9 Hz, 2H), 3.86 (s, 3H),
4.24 (m, 3H), 5.40 (d, J ) 9.0 Hz, 1H), 5.46 (d, J ) 9.0 Hz, 1H),
6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H),
7.56 (m, 1H), 7.61 (d, J ) 8.0 Hz, 1H). MS: 632 (M - Na +
2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.
(R)-3-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluo-
romethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-
1-yl]-1-phenylethylamino}propionic Acid Trifluoroacetate (9).
A mixture of 3-[(2R)-amino-2-phenylethyl)-5-(2-fluoro-3-methox-
yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-
pyrimidinedione (4b, 200 mg, 0.367 mmol), methyl 3-bromopro-
pionate (37.5 mg, 0.44 mmol), and triethylamine (37.1 mg, 0.367
mmol) in acetonitrile (8 mL) was heated to reflux for 16 h. This
solution was cooled to rt and concentrated in Vacuo. The crude
product was purified by chromatography using a 6:4 EtOAc/hexane
to give methyl (R)-3-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-
6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-py-
rimidin-1-yl]-1-phenylethylamino}propionate (20 mg) as an oil.
To a solution of the above product (10 mg, 0.016 mmol) in 0.8
mL/0.2 mL of MeOH/water was added solid LiOH (3.8 mg, 0.16
mmol). The resulting mixture was heated at 45 °C overnight and
concentrated in Vacuo. The crude product was purified on a LC-
MS system to give the titled product as a white foam. HPLC purity:
99.8% (220 nm) and 100% (254 nm). 1H NMR (CDCl3): 2.00 and
2.04 (s, 3H), 2.44-2.56 (m, 1H), 2.88 (m, 3H), 3.80 and 3.83 (s,
3H), 4.19 and 4.32 (d, J ) 15.7 Hz, 1H), 4.65-4.82 (m, 2H), 5.20
(d, J ) 16.8 Hz, 1H), 5.59 and 5.74 (d, J ) 16.8 Hz, 1H), 6.78-6.96
(m, 2H), 7.07 (m, 1H), 7.24 (m, 2H), 7.33-7.56 (m, 6H). MS: 618
(MH+). Anal. (C31H28F5N3O5 ·CF3COOH·4/3H2O): C, H, N.
(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluo-
romethyl]benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-
phenylethylamino}butyric Acid Sodium Salt (6). This compound
was synthesized using a procedure similar to that for 10b from 5b.
1
White powder, HPLC purity: 100% (220 and 254 nm). H NMR
(CD3OD): 1.73 (tt, J ) 6.9, 6.9 Hz, 2H), 2.16 (t, J ) 6.9 Hz, 2H),
2.53 (t, J ) 6.9 Hz, 2H), 3.85 (s, 3H), 4.21-4.37 (m, 3H), 5.23 (s,
2H), 6.81 (m, 1H), 7.07 (m, 2H), 7.29 (m, 5H), 7.43 (brs, 1H),
7.48 (m, 1H), 7.62 (m, 2H). MS: 618 (M - Na + 2H+). Anal.
(C31H27F5N3O5Na·0.7NaOH·2H2O): C, H, N, Na.
(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-chloro-6-fluo-
robenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-
1-phenylethylamino}butyric Acid Sodium Salt (10c). A mixture
of 3-[(2R)-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-
(2-chloro-6-fluorobenzyl)-6-methyl-2,4(1H,3H)-pyrimidinedione
(4c, 4.47 g, 8.7 mmol), ethyl 5-bromobutyrate (1.77 mL, 13.1
mmol), and triethylamine (2.4 mL, 17.4 mmol) in DMF (40 mL)
was heated at 60 °C for 16 h. This solution was cooled to rt, diluted
with ethyl acetate, washed with brine, dried over MgSO4, and
concentrated in Vacuo. The crude product was purified by chro-
matography on silica gel using 3% MeOH in dichloromethane to
give ethyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-chloro-6-
fluorobenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-
1-phenylethylamino}butyrate as an oil.
(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2,6-difluorobenzyl)-
4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethyl-
amino}butyric Acid (10a). To a solution of 3-[(2R)-amino-2-
phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2,6-difluorobenzyl)-
6-methyl-2,4(1H,3H)-pyrimidinedione (4a, 100 mg, 0.2 mmol) in
ethanol (5 mL) was added succinic semialdehyde (20.4 mg, 15%
w/w in water, 0.2 mmol), followed by borane-pyridine (2.5 mL,
0.2 mmol). This mixture was stirred at rt for 15 min and
concentrated in Vacuo. The crude product was purified on a LC-
MS system to give the titled compound as a white form. HPLC
purity: 100% (220 and 254 nm). 1H NMR (CDCl3): 1.66 (m, 2H),
2.21 and 2.23 (s, 3H), 2.33-2.53 (m, 3H), 2.68 (m, 1H), 3.89 (s,
3H), 4.03 (dd, J ) 3.9, 13.2 Hz, 0.5H), 4.15 (dd, J ) 3.0, 11.7 Hz,
0.5H), 4.31-4.58 (m, 2H), 5.25 (d, J ) 15.9 Hz, 0.5H), 5.31 (s,
1H), 5.32 (d, J ) 15.6 Hz, 0.5H), 6.84-7.05 (m, 4H), 7.12 (t, J )
To a solution of the above product (3.85 g, 6.15 mmol) in 40
mL/20 mL of THF/water was added solid LiOH ·H2O (775 mg,
18.45 mmol). The resulting mixture was stirred at rt overnight and
neutralized with 1 N HCl to pH about 7. The product was extracted
with ethyl acetate, and the extract was washed with brine, dried
over MgSO4, and concentrated in Vacuo. The crude product was
purified by chromatography on silica gel using NH4OH/MeOH/
CH2Cl2 (0.5/5/94.5 then 1.5/15/83.5) to give the titled product as a
free acid. This acid (1.54 g) was converted to the sodium salt using
0.1 N NaOH (1 equiv). HPLC purity: 99.6% (220 nm) and 100%
(254 nm). 1H NMR (DMSO-d6): 1.43 (m, 2H), 1.82 (m, 2H), 2.07
(s, 3H), 2.20 (m, 2H), 3.83 (s, 3H), 3.56-4.02 (m, 3H), 5.25 (brs,
2H), 6.57 and 6.73 (m, 1H), 7.07-7.28 (m, 8H), 7.31-7.41 (m,
2H). MS: 598 (MH+). Anal. (C31H29ClF2N3O5Na·2H2O): C, H,
N.