Organic Process Research & Development
Article
kg, 20.4 mol), acetic anhydride (0.12 kg) in acetonitrile (54
kg), and water (3.4 kg) was added dropwise a solution of
sodium periodate (5.24 kg) in water (68 kg) at 30 °C. After
completion of the reaction, a solution of ascorbic acid (12.9
kg) in water (116 kg) was added and concentrated under
reduced pressure. To the concentrate was added water (27 kg)
at 5 °C and the whole was allowed to stand at 5 °C for 1 h.
The precipitate was collected by filtration, washed, and dried
to give 31 (5.78 kg, 89%) as a solid.
sulfoxide (18.6 kg) was added tetrakis(triphenylphosphine)
palladium (466 g) and stirred at 90 °C under carbon monoxide
atmosphere for 5 h. After cooling to room temperature, ethyl
acetate (61 kg) and water (48 kg) were added and insoluble
material was filtered off. Organic layer was separated and ethyl
acetate (91 kg) added. The organic layer was washed with 0.5
N HCl aq and concentrated. To the residue was added 2-
propanol (26.5 kg) and concentrated. The precipitate was
collected by filtration, washed, and dried to give 17 (3.70 kg,
90%) as a solid.
1H NMR (500 MHz, DMSO-d6) δ 7.61 (d, J = 7.6 Hz, 1H),
7.32−7.36 (m, 5H), 6.31 (d, J = 6.9 Hz, 2H), 6.29 (d, J = 7.6
Hz, 1H), 5.09 (s, 2H), 4.91 (m, 1H), 3.80 (s, 3H), 3.73 (d, J =
5.3 Hz, 2H).13C NMR (125 MHz, DMSO-d6) δ 172.42,
162.31, 144.72, 141.24, 137.01, 135.21, 128.14, 128.13, 127.86,
116.87, 87.86, 72.61, 59.05, 53.03. FAB-MS m/z 320 [M + H]+
(4R,12aS)-7-(Benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-
2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione
(19). A solution of 31 (590 g, 1.85 mol) in methanol (5.9
L) was stirred at 70 °C for 30 min, then concentrated under
reduced pressure. To the residue was added toluene (3.0 L),
acetic acid (380 mL), and (R)-3-aminobutan-1-ol (139 g), and
the whole was stirred at 90 °C for 2 h. After cooled to 50 °C,
the reaction mixture was concentrated under reduced pressure
and to the residue was added water (3.0 L) and extracted with
chloroform (3.0 L × 2). The combined extract was
concentrated and ethyl acetate (3.0 L) was added. The
precipitate was collected by filtration, washed with ethyl
acetate, and dried to give 19 (504.4 g, 80%) as a solid.
1H NMR (500 MHz, DMSO-d6) δ 7.69 (d, J = 7.5 Hz, 1H),
7.55 (d, J = 7.5 Hz, 1H), 7.4−7.3 (m, 3H), 6.32 (d, J = 7.5 Hz,
1H), 5.29 (dd, J = 5.7, 5.5 Hz, 1H), 5.03 (d, J = 10.5 Hz, 1H),
5.02 (d, J = 10.5 Hz, 1H), 4.8−4.7 (m, 1H), 4.32 (dd, J = 13.5
4.0 Hz, 1H), 4.11 (dd, J = 13.5, 8.0 Hz, 1H), 4.0−3.8 (m, 2H),
2.0−1.9 (m, 1H), 1.5−1.4 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H).
FAB-MS m/z 341 [M + H]+
(4R,12aS)-7-(Benzyloxy)-9-bromo-4-methyl-3,4,12,12a-
tetrahydro-2H-pyrido [1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-
6,8-dione (32). To a solution of N-bromosuccinimide (1.85
kg, 10.4 mol) in dichloromethane (8.5 kg) was added dropwise
a solution of 19 (3.22 kg, 9.46 mol) in dichloromethane (34.1
kg) at room temperature and stirred for 30 min. After
completion of the reaction, 5% aqueous sodium hydrogen
sulfite solution was added and organic layer was separated. The
organic layer was washed with water (13 kg) and concentrated.
To the residue was added N-methylpyrrolidone (13 kg) and
concentrated. To the residue was added water (35 kg) and the
precipitate was collected by filtration, washed, and dried to give
32 (3.38 kg, 85%) as a solid.
1H NMR (500 MHz, DMSO-d6) δ 10.40 (t, J = 6.0 Hz, 1H),
8.59 (s, 1H), 7.60−7.56 (m, 2H), 7.45−7.30 (m, 4H), 7.24
(td, J = 10.5, 2.5 Hz, 1H), 7.06 (td, J = 8.5, 1.5 Hz, 1H), 5.35
(dd, J = 5.5, 4.0 Hz, 1H), 5.06 (s, 2H), 4.82−4.75 (m, 1H),
4.60−4.52 (m, 3H), 4.36 (dd, J = 13.5, 6.0 Hz, 1H), 3.96 (t, J
= 10.5 Hz, 1H), 3.9−3.8 (m, 1H), 2.0−1.9 (m, 1H), 1.51 (dd,
J = 13.5, 1.5 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). FAB-MS m/z
510 [M + H]+, 1019 [2M + H]+
Dolutegravir Sodium (1). To a solution of 17 (3.70 kg,
7.26 mol) in tetrahydrofuran (55.9 kg) and water (1.9 kg) was
added 5% Pd−C (2.96 kg) in water (7.8 kg) under nitrogen
atmosphere. After replacing the atmosphere with hydrogen, the
whole was stirred at 40 °C under hydrogen atmosphere for 2 h.
The reaction mixture was filtered, and to the filtrate was added
activated carbon (0.37 kg) and stirred at 40 °C for 2 h and
filtered. The filtrate was concentrated under reduced pressure
and to the concentrate was added water (74 kg) dropwise and
stirred for 1 h. The precipitate formed was collected by
filtration, washed with ethanol, and dried under reduced
pressure to give 18 (2.22 kg), which was dissolved in ethanol
(94.6 kg) and water (13.3 kg) at 70 °C. To the solution was
added a solution of sodium hydroxide (212 g) in water (2.6
kg) at 60 °C and stirred at 25 °C for 3 h. The precipitate was
collected by filtration, washed with ethanol (8.8 kg), and dried
under reduced pressure to give 1 (2.22 kg, 69%, 99.9 HPLC
peak area %).
1H NMR (500 MHz, DMSO-d6) δ 10.70 (t, J = 6.0 Hz, 1H),
7.89 (s, 4H), 7.35 (td, J = 8.7, 6.8 Hz, 1H), 7.20 (ddd, J = 10.4,
4.9, 4.2 Hz, 1H), 7.02 (m, 1H), 5.17 (dd, J = 5.1, 3.4 Hz, 1H),
4.81 (m, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 14.0, 3.4
Hz, 1H), 4.16 (dd, J = 14.0, 5.1 Hz, 1H), 3.97 (td, J = 11.9, 2.3
Hz, 1H), 3.81 (m, 1H), 1.87 (m, 1H), 1.38 (m, 1H), 1.24 (d, J
= 7.1 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 177.84,
167.00, 165.94, 161.20 (dd, J = 244.6, 11.9 Hz), 161.01,
159.93 (dd, J = 246.7, 12.0 Hz), 134.21, 130.46 (dd, J = 9.8,
6.3 Hz), 122.85 (dd, J = 15.0, 3.5 Hz), 114.76, 111.14 (dd, J =
20.9, 4.0 Hz), 108.62, 103.57 (t, J = 25.9 Hz), 75.52, 61.81,
53.05, 42.87, 35.22, 29.13, 15.25. FAB-MS m/z 464 [M +
Na]+, 442 [M + H]+
1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.56 (d, J =
7.7 Hz, 2H), 7.4−7.3 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 5.32
(dd, J = 5.4, 3.8 Hz, 1H), 5.05 (d, J = 10.9 Hz, 1H), 5.03 (d, J
= 10.9 Hz, 1H), 4.82−4.74 (m, 1H), 4.39 (dd, J = 13.6, 3.7 Hz,
1H), 4.18 (dd, J = 13.6, 5.4 Hz, 1H), 3.96 (td, J = 11.8, 8.2 Hz,
1H), 3.84 (ddd, J = 11.8, 4.9, 2.4 Hz, 1H), 1.90−1.98 (m, 1H),
1.49 (dq, J = 13.6, 2.4 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). 13C
NMR (125 MHz, DMSO-d6) δ 169.26, 155.56, 148.54, 139.83,
137.31, 129.83, 128.26, 127.91, 127.65, 112.43, 75.60, 72.84,
61.72, 51.44, 44.32, 29.13, 15.60. FAB-MS m/z 419 [M + H]+
(4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-
6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-
pyrazino[2,1-b][1,3]oxazine-9-carboxamide (17). To a sol-
ution of 32 (3.38 kg, 8.06 mol), diisopropylethylamine (2.6
kg) and 2,4-difluorobenzylamine (1.73 kg) in dimethyl
AUTHOR INFORMATION
Corresponding Author
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ORCID
Notes
The authors declare no competing financial interest.
REFERENCES
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(1) (a) Yoshida, H.; Taoda, Y.; Johns, B. A. Synthesis of
Carbamoylpyridone HIV Integrase Inhibitors and Intermediates. World
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX