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while maintaining temperature <5°C. The solution was
cooled to 0°C and NaBH(OAc)3 (6.19 g, 29.22 mmol) was
added in one portion. The mixture was aged 15 min at
0–5°C and then warmed to 20–25°C over 0.5–1 h. The
resulting solution was aged at 20–25°C for 3 h and assayed
by HPLC (Method G). [Compound retention times:
penultimate (6.5 min), aldehyde (9.1 min), bicyclic aminal
18 (19.2 min), free base 1 (23.0 min)]. Upon completion
of the reaction (<2 A% penultimate remains), H2O (30
mL) was added. The solution was warmed to 50°C and
seeded with pure free base (1 wt%). The thin slurry was
aged 0.5 h at 50°C and H2O (270 mL) was added over
30 min. The resulting thick slurry was aged 1 h at 50°C
and then filtered. The filter-cake was washed with H2O
(150 mL) and dried under N2 for 4–6 h. The filter-cake
was further dried to a constant weight in a vacuum oven
(60°C, 23¦ Hg). Isolated 19.2 g (96.2 wt%, 91.6% yield,
<1.5% loss to ML’s and wash) of an off-white crystalline
solid.
added HOAc (0.29 mL, 5.0 mmol). The solution was aged
at 23°C for 48 h. Compound 18 formed in ꢀ60%
conversion. 1H NMR (600 MHz, DMF-d7-selected data)
l 7.16 (d, J=3.4 Hz, 1H), 6.60 (d, J=3.4 Hz, 1H), 5.70
(s, 1H), 4.95 (dq, J=15.5, 9.4 Hz, 1H), 3.57 (dq, J=15.5,
9.4, 1H); 13C NMR (150 MHz, DMF-d7) l 175.9, 166.4,
154.6, 152.9, 152.6, 148.6, 147.3, 140.5, 137.1, 130.0,
129.2, 129.0, 128.3 (2C), 126.2, 125.4 (q, J=280.8 Hz),
122.7, 120.4, 119.7, 115.9, 111.6, 110.2, 75.1, 68.8, 65.5,
64.4, 63.1, 57.2, 53.1, 47.7, 47.0, 46.8, 45.0, 42.9(q, J=42.9
Hz), 39.6, 37.8.
4.15. (2S)-1-((2S,4R)-4-Benzyl-5-{[(3S,4S)-3-hydroxy-
3,4-dihydro-2H-chromen-4-yl]-amino}-2-hydroxy-5-
oxopentyl)-4-{[5-(5-chloropyridin-2-yl)-2-furyl]methyl}-N-
(2,2,2-trifluoroethyl)piperazine-2-carboxamide bisben-
zenesulfonic acid salt 1·2BSA
A solution of 0.1 g/mL benzene sulfonic acid in EtOH
(31.4 mL, 19.83 mmol, KF<800 ug/mL) was added to a
23°C slurry of free base 1 (10.0 g, 13.22 mmol) in EtOH
(36 mL). The resulting slurry was warmed to 50°C and
the resulting solution was then seeded with crystalline 1
bis besylate salt (70 mg, 0.5 wt%). Additional benzene
sulfonic acid in EtOH (13.0 mL, 7.93 mmol, 2.1 equiv.
total) was added over 1 h while maintaining the slurry
at 50°C. The thick slurry was aged 0.5 h at 50°C, 1 h at
23°C and then filtered. The filter-cake was washed with
EtOH (30 mL). The solid was dried in a vacuum oven
at 40°C (23¦Hg, 31 h). Isolated 11.9 g (HPLC Method
G, >98.5 A%, 84% yield) of a white crystalline solid. Mp
139–142°C (decomposed); [h]2D5=+15.9 (c 1, methanol);
IR: 3298, 3061, 1700, 1653, 1636, 1540, 1213, 1154, 1016,
MeOH (425 mL) and crude free base 1 (12.98 g, 17.16
mmol) were charged to a vessel and the resulting slurry
was warmed to 60–64°C. Darco G-60 (2.6 g) was charged
to the hot MeOH solution and aged 1 h at 55°C. The hot
slurry was filtered through solka floc and the filter-cake
was washed with MeOH (142 mL). The filtrate was
concentrated to a total volume of 284 mL (18–20°C, 80–85
torr) and the resulting slurry was warmed to 60–64°C to
dissolve all solids. The batch was seeded with pure free
base (1.0 wt%) at 58°C, aged at 55–58°C for 0.5 h, and
then slowly cooled to 20–23°C over 1 h. The slurry was
solvent switched to n-PrOH by constant volume distilla-
tion (distillation complete when <5% MeOH remained;
final volume: 210 mL). The slurry was filtered at 20–25°C
and dried to a constant weight in a vacuum oven (60°C,
23¦ Hg). Isolated 11.2 g and analyzed by HPLC (Method
G, >99.4 A%, >99 wt.%, 86% yield from crude 1, 6–8%
loss to ML’s and wash). Mp 203–204°C; [h]2D5=+20.0
(c=1, 0.01N HCl/methanol); IR: 3304, 2958, 2820, 1658,
1212, 1152, 1018, 798, 638, 499 cm−1; 1H NMR
((CD3)2SO, 400 MHz): l=8.60 (d, J=2.4 Hz, 1H), 8.43
(t, J=6.5 Hz, 1H), 7.95 (dd, J=2.4, 8.7 Hz, 1H), 7.81
(d, J=8.8 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.27–7.20
(m, 4H), 7.18–7.14 (m, 1H), 7.10–7.00 (m, 3H), 6.78 (t,
J=7.4 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.50 (d, J=3.3
Hz, 1H), 5.12 (dd, J=3.8, 8.9 Hz, 1H), 5.09 (d, J=3.6
Hz, 1H), 4.59 (d, J=4.3 Hz, 1H), 4.16–4.00 (m, 2H),
3.95–3.86 (m, 1H), 3.84–3.76 (m, 1H), 3.75–3.73 (m, 1H),
3.67 (bs, 1H), 3.62 (s, 2H), 3.05–2.90 (m, 4H), 2.70–2.58
(m, 3H), 2.43 (t, J=9.6 Hz, 1H), 2.37–2.18 (m, 4H), 1.98
(t, J=11.5, 1H), 1.17 (t, J=10.8 Hz, 1H); 13C NMR
((CD3)2SO): l=175.1, 171.7, 153.9, 153.2, 151.5, 148.1,
147.0, 139.9, 136.8, 128.9, 128.4, 128.0, 126.0, 125.8,
122.4, 119.9, 119.3, 115.5, 111.6, 110.3, 68.3, 65.5, 63.3,
61.6, 53.7, 51.1, 50.3, 46.8, 43.8, 37.5; HRMS (ESI): m/z
756.2781 ([M+H]+, C38H42ClF3N5O6, calcd 756.2776).
1
729, 612, 503 cm−1; H NMR ((CD3)2SO, 400 MHz):
l=9.39 (bs, 1H), 8.64 (d, J=2.5, 1H), 8.00 (ddd, J=0.7,
2.4, 8.6 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.76 (d, J=8.5
Hz, 1H), 7.66–7.60 (m, 4H), 7.37–7.30 (m, 6H), 7.29–7.16
(m, 7H), 7.14–7.00 (m, 2H), 6.81 (t, J=7.5 Hz, 1H), 6.76
(d, J=3.2 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 7.00–5.80
(broad, 2H), 5.14 (dd, J=3.7, 8.8 Hz, 1H), 4.21–3.90 (m,
9H), 3.76 (s, 1H), 3.69 (bs, 1H), 3.44 (d, J=11.2 Hz, 1H),
3.30 (d, J=11.1 Hz, 1H), 3.20 (t, J=11.2 Hz, 1H),
3.05–2.90 (m, 6H), 2.63 (m, 1H), 1.74 (t, J=10.8 Hz, 1H),
1.31 (t, J=11.6 Hz, 1H); 13C NMR ((CD3)2SO): l=174.5,
166.6, 154.1, 153.1, 148.3, 147.7, 146.6, 139.6, 137.1,
129.7, 129.0, 128.9, 128.8, 128.2, 128.1, 127.9, 126.1,
125.9, 125.6, 123.1, 122.3, 120.3, 120.0, 115.6, 110.7, 68.5,
65.0, 63.3, 59.9, 51.7, 48.0, 46.9, 43.2, 37.4. Anal. calcd
for C50H53ClF3N5O12S2: C, 55.99; H, 4.98; Cl, 3.31; F,
5.31; N, 6.53; O, 17.90; S, 5.98. Found: C, 55.88; H, 4.94;
Cl, 3.31; F, 5.35; N, 6.55; O, 17.95; S, 6.02.
Acknowledgements
4.14. (2R,4S)-2-Benzyl-5-[(5S)-2-[5-(5-chloropyridin-2-
yl)-2-furyl]-4-oxo-3-(2,2,2-trifluoroethyl)-1,3,6-triazabi-
cyclo[3.3.1]non-6-yl]-N-[(3S,4S)-3-hydroxy-3,4-dihydro-
2H-chromen-4-yl]-4-hydroxypentanamide 18
The authors thank Dr. J. Wang and Dr. F. P. Gort-
sema for performing reaction calorimetry experiments
on the hydrogenation of pyrazine amide 9, and P.
Dormer, and L. DiMichele for assistance with NMR
interpretation.
To a solution of penultimate 14 (0.565 g, 1.0 mmol) and
aldehyde 16 (0.228 g, 1.1 mmol) in DMF-d7 (2.3 mL) was