Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. NMR Spectroscopy
2.3. HPLC Analyses
2.4. Structure Description
2.5. Conformational Analysis
3. Materials and Methods
3.1. General
3.2. Synthesis of 1 from 3
3.2.1. 1-(2-fluoro-6-(trifluoromethyl)benzyl) urea (4)
3.2.2. 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (5)
3.2.3. 5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (6)
3.2.4. 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (7)
3.2.5. (R)-2-[(tert-butoxy-carbonyl)amino]-2-phenylethyl methane-sulfonate (10)
3.2.6. (R)-3-(amino(phenyl)methyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine 2,4(1H,3H)-dione (8)
3.2.7. Ethyl (R)-4-(((5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)(phenyl)methyl)amino)butanoate (9)
3.2.8. Elagolix Sodium Salt (1)
3.3. NMR Spectroscopy
3.4. HPLC Analyses
- −
- Chiral HPLC analysis: a Merck-Hitachi (Hitachi Ltd., Tokyo, Japan), equipped with a UV detector model L-4250, pump system model L-6200 and a chromato-integrator model D-2500. The column employed in the analyses was a Phenomenex Lux-Cellulose 1 (Phenomenex, Torrance, CA, USA). The dimension of the column is 250 mm × 4.6 mm, 3 µm. The elution was in isocratic mode with the indicated eluant and flow. All the samples were measured at λ = 254 nm and 25 °C.
- −
- RP-HPLC analysis: Agilent 1100 system (Agilent Technologies, Waldbronn, Germany) equipped with a Zorbax SB-C18 column (150 mm × 3.0 mm, 3.5 µm) for 1 and with a Supelco Discovery C18 (250 mm × 4.6 mm, 5.0 µm) for 7.
3.5. X-ray Analysis
3.6. Conformational Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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1H | 5 | 6 | 7 | 8 | 9 | 1 |
---|---|---|---|---|---|---|
1 | / | / | / | / | / | / |
2 | / | / | / | / | / | / |
3 | 8.97 (brs) | Exchanged with CD3OD | 8.52 (brs) | / | / | / |
4 | / | / | / | / | / | / |
5 | 5.59 (s) | / | / | / | / | / |
6 | / | / | / | / | / | / |
7 | 5.36 (s) | 5.38 (s) | 5.47 (s) | 5.50 (m) | 5.47 (m) | 5.43 (m) |
8 | / | / | / | / | / | / |
9 | / | / | / | / | / | / |
10 | 7.25 (dd, J = 12.3 and 8.5 Hz) | 7.20 (dd, J= 11.7 and 8.3 Hz) | 7.28 (dd, J = 11.8 and 8.3 Hz) | 7.26 (m, overlapped with 28) | 7.29 (m, overlapped with 28) | 7.44 (m) |
11 | 7.42 (m) | 7.37 (m) | 7.42 (m) | 7.41 (m, overlapped with 26 and 26’) | 7.41 (m) | 7.53 (td, J = 8.1, 5.0 Hz) |
12 | 7.54 (d, J = 7.9 Hz) | 7.48 (d, J = 7.8 Hz) | 7.54 (d, J = 7.9 Hz) | 7.55 (d, J = 7.9 Hz) | 7.54 (d, J = 7.9 Hz) | 7.62 (d, J = 7.9 Hz) |
13 | / | / | / | / | / | / |
14 | / | / | / | / | / | / |
15 | 2.15 (s) | 2.35 (s) | 2.05 (s) | 2.07 (s) | 2.07 and 2.06 * | 2.085 (s) and 2.076 (s) * |
16 | / | / | / | / | / | / |
17 | / | / | / | / | / | / |
18 | / | / | / | / | / | / |
19 | / | / | 6.97 (m) | 6.97 (td, J = 8.2 and 1.3 Hz) | 6.97 (tt, J = 8.1 and 1.6 Hz) | 7.10 (n.d., overlapped with 20) |
20 | / | / | 7.10 (dd, J = 9.0 and 7.9 Hz) | 7.11 (tdd, J = 8.0, 2.8, and 1.3 Hz) | 7.11 (tdd, J = 8.0, 4.6, and 1.3 Hz) | 7.11 and 7.14 (n.d., overlapped with 19) |
21 | / | / | 6.81 (m) | 6.85 (td, J = 6.2 and 1.5 Hz) and 6.78 (td, J = 6.2 and 1.4 Hz) * | 6.83 (ddd, J = 7.7, 6.0, and 1.6 Hz) and 6.76 (ddd, J = 7.7, 6.0, and 1.6 Hz) * | 6.76 (m) and 6.61 (m) * |
22 | / | / | 3.88 (s) | 3.89 (s) | 3.889 (s) and 3.886 (s) * | 3.883 (s) and 3.880 (s) * |
23 | / | / | / | 4.29 (m o ddd, J = 16.2, 13.1, 9.8 Hz, Ha) and 4.11 (m, Hb) | 4.28 (m, Ha) and 4.04(m, Hb) | 4.26–4.07 (m) |
24 | / | / | / | 4.42 (dd, J = 9.8 and 4.5 Hz) | 4.12 (m) | 4.11 (n.d.) |
25 | / | / | / | / | / | / |
26 and 26′ | / | / | / | 7.41 (m, overlapped with 11) | 7.37 (m) | 7.29 (n.d., overlapped with 28) |
27 and 27′ | / | / | / | 7.32 (m) | 7.30 (m, overlapped with 10) | 7.27 (n.d., overlapped with 26 and 26’) |
28 | / | / | / | 7.27 (m, overlapped with 10) | 7.24 (m) | 7.22 (m) |
29 | / | / | / | 2.13 | 1.63 (brs) | / |
30 | / | / | / | / | 2.46 (m, Ha) and 2.38 (m, Hb) | 2.40 (m) |
31 | / | / | / | / | 1.68 (m) | 1.75 (m, Ha) and 1.68 (m, Hb) |
32 | / | / | / | / | 2.29 (m) | 2.09 (m, overlapped with 15) |
33 | / | / | / | / | / | / |
CH2CH3 | / | / | / | / | 4.084 (q, J = 7.1Hz,) and 4.082 (q, J = 7.1Hz) * | / |
CH2CH3 | / | / | / | / | 1.21 (t, J = 7.1 Hz) | / |
13C | 5 | 6 | 7 | 8 | 9 | 1 |
---|---|---|---|---|---|---|
1 | / | / | / | / | / | / |
2 | 151.7 | 150.8 | 151.0 | 152.3 | 152.3 and 152.2 * | 153.3 and 153.2 * |
3 | / | / | / | / | / | / |
4 | 162.4 | 159.6 | 161.2 | 161.8 and 161.6 * | 161.7 and 161.6 * | 163.5 and 163.3 * |
5 | 102.5 | 99.2 | 108.8 | 108.3 and 108.2 * | 108.3 and 108.2 * | 109.3 and 109.2 * |
6 | 153.6 | 151.6 | 151.9 | 149.9 and 149.8 * | 149.7 and 149.6 * | 152.6 and 152.5 * |
7 | 41.1 (m) | 42.5 (m) | 41.8 (m) | 42.7 (brs) | 42.7 (brs) | 44.1 (brs) |
8 | 121.8 (d, J = 11.6 Hz) | 121.2 (d, J = 11.3 Hz) | 121.8 (d, J = 11.1 Hz) | 122.0 (d, J= 11.4 Hz) | 122.1 (d, J = 11.3 Hz) | 123.6 (overlapped with 12 and 16) |
9 | 161.4 (d, J = 250.0 Hz) | 161.1 (d, J = 249.6 Hz) | 161.4 (d, J = 250.0 Hz) | 161.3 (d, J = 249.5 Hz) | 161.3 (d, J = 250.0 Hz) | 162.8 (d, J =248.0 Hz) |
10 | 120.9 (d, J = 24.0 Hz) | 120.9 (d, J = 24.0 Hz) | 121.0 (d, J = 24.4 Hz) | 120.9 (d, J = 24.1 Hz) | 120.9 (d, J = 24.4 Hz) | 122.15 (d, J = 24.3 Hz) and 122.19 (d, J = 24.3 Hz) * |
11 | 129.5 (d, J = 10.0 Hz) | 129.6 (d, J = 9.7 Hz) | 129.5 (d, J = 9.8 Hz) | 129.3 (d, J = 9.8 Hz) | 129.3 (d, J = 9.6 Hz) | 130.9 and 130.8 * |
12 | 122.6 (m) | 122.5 (m) | 122.6 (m) | 122.6 (m) | 122.5 (m) | 123.7 (overlapped with 8 and 16) |
13 | 129.6 (dd, J = 30.0 and 3.6 Hz; partially hidden by 11) | 129.3 (dd, J = 30.9 and 3.7 Hz; | 129.6 (dd, J = 30.9 and 4.0 Hz) | 129.5 (dd, J = 31.0 and 3.1, partially overlapped with 11) | 129.3 (dd, J = 30.2 and 3.0 Hz) | 130.6 (dd, J = 31.1 and 3.3 Hz) |
14 | 123.4 (dd, J = 273.6 and 4.0 Hz) | 123.3 (dd, J = 274.3 and 4.2 Hz) | 123.5 (dd, J = 273.8 and 3.9 Hz) | 123.5 (dd, J = 273.6 and 3.8 Hz) | 123.5 (dd, J = 271.1 and 3.7 Hz) | 125.1 (dd, J = 273.3 and 3.8 Hz) |
15 | 20.1 | 20.1 | 17.9 | 17.8 | 17.8 | 18.1 |
16 | / | / | 121.5 (d, J = 13.6 Hz) | 122.3 (d, J = 13.7 Hz) and 122.2 (d, J = 13.7 Hz) * | 122.37 (d, J = 13.8 Hz) and 122.35 (d, J = 13.8 Hz) | 123.8 (overlapped with 8 and 12) |
17 | / | / | 149.9 (d, J = 246.4 Hz) | 150.2 (d, J = 246.3 Hz) and 150.1 (d, J = 246.3 Hz) * | 150.23 (d, J = 245.5) and 150.17 (d, J = 245.5) | 151.8 (d, J = 245.4 Hz) |
18 | / | / | 148.0 (d, J = 11.0 Hz) | 148.0 (d, J = 11.0 Hz) | 148.0 (d, J = 11.0 Hz) | 149.5 (d, J = 11.2 Hz) |
19 | / | / | 113.5 | 113.3 | 113.2 | 114.8 |
20 | / | / | 123.8 | 123.8 (overlapped with 21) | 123.80 (s) and 123.76 (s) * | 125.1 (s) and 125.0 (s) * |
21 | / | / | 123.9 (d, J = 4.6 Hz) | 123.9 and 123.8 (overlapped with 20) * | 123.92 (s) and 123.85 (s) * | 125.0 and 124.9 * |
22 | / | / | 56.3 | 56.2 | 56.2 | 56.8 |
23 | / | / | / | 49.10 and 49.14 * | 47.7 and 47.6 * | 48.1 and 47.9 * |
24 | / | / | / | 54.1 and 54.2 * | 60.9 and 60.8 * | 62.2 and 62.0 * |
25 | / | / | / | 143.7 and 143.6 * | 141.92 (s) and 141.89 (s) * | 142.1 and 141.9 * |
26 and 26’ | / | / | / | 126.4 and 126.3 * | 127.2 and 127.1 (overlapped with 28) * | 128.7 |
27 and 27’ | / | / | / | 128.5 and 128.4 * | 128.4 and 128.3 * | 129.4 |
28 | / | / | / | 127.3 and 127.2 * | 127.2 (overlapped with 26 and 26′) | 128.5 |
29 | / | / | / | / | / | / |
30 | / | / | / | / | 46.51 (s) and 46.47 (s) * | 48.7 |
31 | / | / | / | 25.4 | 27.86 (s) and 27.83 (s) * | |
32 | / | / | / | / | 32.0 | 37.03 (s) and 37.00 (s) * |
33 | / | / | / | / | 173.7 60.1 | 182.3 |
CH2CH3 | / | / | / | / | / | |
CH2CH3 | / | / | / | / | 14.2 | / |
15N | 5 | 6 | 7 | 8 | 9 | 1 |
---|---|---|---|---|---|---|
1 | 136.7 | 137.9 | 134.3 | 134.3 | 135.5 | 137.1 |
3 | 154.3 b | 153.4 b | 151.9 b | 160.1 | 161.3 | 160.5 |
29 | / | / | / | 31.2 | 43.6 | 46.3 |
13C | HMBC (13C→1H) |
---|---|
C-2 | H-7 and H-23 |
C-4 | H-23 and H-15 (weak) |
C-5 | H-21 and H-15 |
C-6 | H-15 |
C-8 | H-7, H-10, and H-12 |
C-9 | H-7, H-10, and H-11 |
C-13 | H-7 and H-11 |
C-14 | H-12 |
C-16 | H-20 |
C-17 | H-19 and H-21 |
C-18 | H-20 and H-22 |
C-25 | H-23, H-24, H-27, and H-27’ |
C-33 | H-31 and H-32 |
Conformers | τ1 (°) | τ2 (°) | τ3 (°) | τ4 (°) | Gas Phase ΔE (kcal/mol) | Gas Phase (%) |
---|---|---|---|---|---|---|
1A | −81.6 | −48.5 | −132.0 | 49.1 | 4.35 | 0.0 |
1B | −70.0 | 147.8 | −130.0 | 49.7 | 6.84 | 0.0 |
1C | 96.0 | −54.0 | −125.0 | 70.0 | 0.67 | 20.5 |
1D | 111.8 | 134.3 | −133.0 | 52.5 | 4.60 | 0.0 |
1E | −80.5 | −47.0 | −61.3 | −52.4 | 4.67 | 0.0 |
1F | −69.4 | 150.3 | −55.0 | −55.5 | 7.09 | 0.0 |
1G | 113.0 | 136.0 | −60.5 | −55.6 | 5.01 | 0.0 |
1H | 93.2 | −62.1 | −64.1 | −55.6 | 1.90 | 2.6 |
1I | 94.5 | −53.6 | 61.3 | −142.6 | 2.26 | 1.4 |
1J | 118.5 | 147.4 | 59.4 | −140.8 | 4.86 | 0.0 |
1K | −74.0 | −40.3 | 67.8 | −141.2 | 4.78 | 0.0 |
1L | −69.1 | 148.9 | 60.5 | −142.9 | 3.69 | 0.1 |
1M | 92.6 | −61.9 | −110.0 | −134.5 | 0.00 | 63.9 |
1N | 113.6 | 146.5 | −77.5 | 147.4 | 3.98 | 0.1 |
1O | −85.9 | −51.6 | −115.4 | −136.4 | 3.58 | 0.2 |
1P | −70.9 | 148.7 | −75.9 | 146.3 | 5.33 | 0.0 |
1Q | −81.0 | −46.4 | −75.4 | 142.8 | 3.64 | 0.1 |
1R | −71.1 | 148.9 | −75.2 | 147.0 | 5.40 | 0.0 |
1S | 92.7 | −55.0 | −76.1 | 139.9 | 1.09 | 10.1 |
1T | 113.9 | 146.9 | −77.6 | 147.5 | 3.93 | 0.1 |
1U | −86.3 | −49.9 | 56.0 | 53.0 | 4.53 | 0.0 |
1V | −70.1 | 145.9 | 51.1 | 55.2 | 3.67 | 0.1 |
1W | 93.5 | −53.5 | 49.9 | 53.8 | 2.77 | 0.6 |
1X | 114.2 | 142.7 | 51.3 | 53.6 | 5.32 | 0.0 |
Code | τ1 | τ2 | τ3 | τ4 | τ5 | Water ΔE (kcal/mol) | Water (%) |
---|---|---|---|---|---|---|---|
7 (crystal structure) | −105.5 | −144.7 | 110.4 | ||||
1M−A | 87.7° | −63.3° | −104.7° | −133.9° | −111.8° | 0.00 | 83.6 |
1M−C | 91.3° | −60.2° | −106.7° | −132.6° | 75.2° | 2.07 | 2.6 |
1M−D | 92.9° | −60.3° | −110.0° | −135.0° | 126.3° | 1.06 | 13.8 |
Conformer | t6 | Distance CH22 – H19 (Å) | Gas Phase ΔE (kcal/mol) | Gas Phase (%) | Methanol ΔE (kcal/mol) | Methanol (%) |
---|---|---|---|---|---|---|
1M-A | 0 | 2.56 | 0.00 | 44.5 | 0 | 86.0 |
1M-A (I) | −66 | 3.60 | 0.29 | 27.5 | 1.62 | 5.6 |
1M-A (II) | +66 | 3.60 | 0.27 | 28.0 | 1.38 | 8.4 |
1M-D | 0 | 2.56 | 0.22 | 30.5 | 0.00 | 84.5 |
1M-D (I) | −66 | 3.60 | 0.32 | 25.6 | 1.36 | 8.5 |
1M-D (II) | +66 | 3.60 | 0.00 | 43.9 | 1.48 | 7.0 |
Crystal Data | |
---|---|
Chemical formula | C20H15F5N2O3 |
Mr | 426.34 |
Crystal system, space group | Orthorhombic, P bca |
a, b, c (Å) | 11.165 (2), 11.073 (2), 30.367(6) |
V (Å3) | 3754.2(13)) |
Z | 8 |
F (000) | 1744 |
Density (g/cm3) | 1.509 |
Temperature (K) | 298 |
Radiation type | Mo-Kα (λ = 0.71073 Å) |
µ (mm−1) | 1.135 |
Crystal size (mm) | 0.06 × 0.03 × 0.02 |
Data collection | |
Diffractometer | Bruker-Axs Smart-Apex CCD |
Tmin, Tmax | 0.893, 1.000 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 29,138, 4175, 1715 |
Rint | 0.0298 |
Structure refinement | |
R, wR2, S | 0.0437 (I > 2σ(I)) and 0.1119 (all), 0.0973 (I > 2σ(I)) and 0.1126 (all), 0.760 (all) |
No. of parameters | 271 |
No. of restraints | 0 |
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Ciceri, S.; Colombo, D.; Fassi, E.M.A.; Ferraboschi, P.; Grazioso, G.; Grisenti, P.; Iannone, M.; Castellano, C.; Meneghetti, F. Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study. Molecules 2023, 28, 3861. https://doi.org/10.3390/molecules28093861
Ciceri S, Colombo D, Fassi EMA, Ferraboschi P, Grazioso G, Grisenti P, Iannone M, Castellano C, Meneghetti F. Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study. Molecules. 2023; 28(9):3861. https://doi.org/10.3390/molecules28093861
Chicago/Turabian StyleCiceri, Samuele, Diego Colombo, Enrico M. A. Fassi, Patrizia Ferraboschi, Giovanni Grazioso, Paride Grisenti, Marco Iannone, Carlo Castellano, and Fiorella Meneghetti. 2023. "Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study" Molecules 28, no. 9: 3861. https://doi.org/10.3390/molecules28093861
APA StyleCiceri, S., Colombo, D., Fassi, E. M. A., Ferraboschi, P., Grazioso, G., Grisenti, P., Iannone, M., Castellano, C., & Meneghetti, F. (2023). Elagolix Sodium Salt and Its Synthetic Intermediates: A Spectroscopic, Crystallographic, and Conformational Study. Molecules, 28(9), 3861. https://doi.org/10.3390/molecules28093861