Pippel et al.
JOCArticle
(2R,4S )-1-[2-(4-Cyclobutyl[1,4]diazepane-1-carbonyl)-4-(3-flu-
orophenoxy)pyrrolidin-1-yl]ethanone (1 HCl). To a 5-L jacketed
stirred at room temperature for 30 min. After the mixture was
stirred at 0 °C for an additional 2 h, the resulting solids were
collected by filtration and washed with 90 mL of IPA to provide the
title compound as a white solid (80 g, 52%).
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reactor equipped with an overhead mechanical stirrer, nitrogen
inlet, and thermocouple probe were added (2R,4R)-1-[2-(4-cyclo-
butyl[1,4]diazepane-1-carbonyl)-4-hydroxypyrrolidin-1-yl]etha-
none (138.77 g, 448.5 mmol) and dichloromethane (4.3 L). To
the stirring solution were added 3-fluorophenol (41.83 mL,
462.0 mmol) and resin-supported triphenylphosphine (339.33 g,
Polymer Laboratories, PL-TPP, 1.52 mmol/g, 515.8 mmol).
Finally, diisopropyl azodicarboxylate (91 mL, 462.0 mmol)
was added dropwise over 15 min. The mixture was allowed to
stir at room temperature for 15 h, and then the resin was
removed by filtration and washed with dichloromethane (4 L).
The resulting filtrate was concentrated to dryness and parti-
tioned between water (2 L) and MTBE (2 L). After separation of
the layers, the aqueous layer was further extracted with MTBE
(2 Â 1.8 L). The combined organics were concentrated to 2 L and
then extracted with 1 N HCl (2 L). The acidic aqueous layer was
washed once with MTBE (1 L) and then basified to pH >12 with
50% NaOH(aq) (118 mL). The aqueous layer was extracted with
dichloromethane (2 Â 1.5 L), and the combined organics were
dried over MgSO4, filtered, and concentrated to a yellow oil
(129.0 g, 16.9 wt % dichloromethane, 1.4 wt % MTBE, 1.1 wt %
DIAD byproduct, 80.5 wt % 1 (103.8 g, 57%). The material was
purified further through flash chromatography (0-5% 2 M
NH3 in MeOH/DCM) (96.3 g, 53%). The material was taken up
into ethanol and concentrated to remove all dichloromethane
and methanol. Finally, dissolution into water with 1 equiv of 1 N
(2R,4R)-1-[2-([1,4]Diazepane-1-carbonyl)-4-hydroxypyrrol-
idin-1-yl]ethanone (7). To a 5-L jacketed reactor equipped with an
overhead mechanical stirrer, nitrogen inlet, thermocouple probe,
and reflux condenser were added (1R,4R)-N-acyl-2-oxa-5-azabi-
cyclo[2.2.1]heptan-3-one (310.3 g, 2 mol), homopiperazine (500.85 g,
5 mol), and tert-amyl alcohol (3 L). The mixture was warmed to
90 °C for 15 h and then cooled to room temperature. The mixture
was then concentrated under reduced pressure to a mass of 1280.16
g. During concentration, white solids formed. The solids were
filtered, washed with 1 L of ethyl acetate, and dried on the filter
to provide the title compound as a white crystalline solid (379.7 g,
1.6 wt % tert-amyl alcohol, 1.8 wt % homopiperazine, 96.6 wt % 7
(367 g, 72%)): 1H NMR (400 MHz, CDCl3) δ5.96 (s, 1H), 4.88 (dd,
J = 14.5, 9.7, 1H), 4.42 (bs, 1H), 3.91-3.63 (m, 5H), 3.54-3.40 (m,
1H), 3.28 (ddd, J = 13.7, 7.3, 4.5, 0.44H), 3.12-2.74 (m, 4H), 2.27
(ddd, J= 14.7, 10.2, 5.2, 1H), 2.17-1.95 (m, 4.56H), 1.82-1.72 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 174.1, 170.3, (72.1 and 72.1),
(58.50 and 58.46), (55.52 and 55.48), (51.6, 50.2, 49.3, 48.9, 48.5,
48.3, 48.0, 47.0 signals for 4 carbons), (37.58 and 37.55), (30.6 and
29.9), 22.8. Anal. Calcd for C12H21N3O3: C, 56.45; H, 8.29; N,
16.46. Found: C, 56.33; H, 8.46; N, 16.27.
(2R,4R)-1-[2-(4-Cyclobutyl[1,4]diazepane-1-carbonyl)-4-hydro-
xypyrrolidin-1-yl]ethanone (6). To a 5-L jacketed reactor equipped
with an overhead mechanical stirrer, nitrogen inlet, and thermo-
couple probe were added (2R,4R)-1-[2-([1,4]diazepane-1-carbonyl)-
4-hydroxypyrrolidin-1-yl]ethanone (370 g, 1.4 mol 7, 0.07 mol
homopiperazine), cyclobutanone (137 mL, 1.84 mmol), and 1,2-
dichloroethane (3.7 L). The mixture was stirred for 1 h, and then
sodium triacetoxy borohydride (422.4 g, 1.99 mol) was added in five
portions over 2 h. After the reaction mixture was stirred overnight at
room temperature, the mixture was quenched with 50% NaOH(aq)
(318.4 g solution, 3.98 mol). After the mixture was stirred for 2 h,
magnesium sulfate was added (264.19 g). After an additional 1.5 h of
stirring, the solids were removed by filtration and the filtrate was
dried with additional magnesium sulfate, filtered, and concentrated
to a final mass of 435.57 g, ∼73 wt % 6 (318 g, 73%). Additional
purification was achieved by flash chromatography (2.5 kg of silica
gel, 5% 2 M NH3 in MeOH/95% DCM) to give the title compound
as an oil (277.4 g, 64%). To remove all traces of methanol prior to
the final step, the compound was taken up in THF and reconcen-
trated: 1H NMR (400 MHz, CDCl3) δ 6.16-5.95 (m, 1H), 4.90 (dd,
J = 9.6, 4.6, 1H), 4.49-4.32 (m, 1H), 3.99-3.55 (m, 5.5H), 3.53-
3.42 (m, 0.5H), 2.90 (tt, J = 15.7, 8.0, 1H), 2.72 (ddd, J = 13.0, 7.5,
2.5, 0.5H), 2.63-2.34 (m, 3.5H), 2.26 (ddd, J = 14.4, 9.7, 5.0, 1H),
2.11-1.50 (m, 12H); 13C NMR (151 MHz, CDCl3) two major con-
formers, δ (173.8 and 173.6), (169.9 and 169.8), 71.7, (59.6 and
59.5), (55.1 and 55.0), (52.4 and 52.0), (50.4 and 50.3), (48.5 and
47.3), (46.4 and 45.5), (37.2 and 37.1), (28.02, 28.00, 27.95, and
26.8, signals for 2 carbons), 22.4, (13.42, 13.39). Anal. Calcd for
C16H17N3O3: C, 62.11; H, 8.80; N, 13.58. Found: C, 61.28; H, 8.79;
N, 13.70.
HCl(aq) and lyophilization provided 1 HCl as a somewhat
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hygroscopic, noncrystalline, white solid (with ∼10000 ppm
EtOH): 1H NMR (500 MHz, CDCl3) δ 12.38 (bs, 1H),
7.28-7.20 (m, 1H), 6.75-6.67 (m, 1H), 6.67-6.61 (m, 1H),
6.61-6.53 (m, 1H), 5.06 (bs, 1H), 4.90-4.65 (m, 1H), 4.40-4.23
(m, 1H), 4.22-4.06 (m, 1H), 4.06-3.90 (m, 1.25H), 3.80-3.73
(m, 1H), 3.66-3.46 (m, 2H), 3.46-3.18 (m, 3.5H), 3.06-2.93 (m,
1.25H), 2.93-2.62 (m, 3H), 2.53-2.37 (m, 1H), 2.37-2.10 (m,
4H), 2.07-2.04 (m, 3H), 1.98-1.87 (m, 1H), 1.76-1.57 (m, 1H);
13C NMR (151 MHz, CDCl3) two major conformers δ (172.3
and 171.9), 169.5, 163.3 (d, JC-F = 246 Hz), (157.7 [d, JC-F
=
11 Hz] and 157.8 [d, JC-F = 11 Hz]), 130.5 (d, JC-F = 10 Hz),
110.9, (108.32 [d, JC-F = 21 Hz] and 108.28 [d, JC-F = 21 Hz]),
(103.2 [d, JC-F = 25 Hz] and 103.1 [d, JC-F = 25 Hz]), 76.1,
(60.1 and 60.0), (54.8 and 54.3), (53.45 and 53.39), (51.2, 50.9),
(49.4 and 48.9), (45.2 and 43.2), (43.4 and 41.3), (35.1 and 34.9),
(25.70, 25.67, 25.50, and 25.48), (23.5 and 22.2), 22.2, (12.9
and 12.8). Anal. Calcd for C22H31ClFN3O3 0.15H2O: C, 59.69;
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H, 7.13; N, 9.49; Cl, 8.01. Found: C, 59.56; H, 7.24; N, 9.37;
Cl, 8.14.
Supporting Information Available: 1H NMR and 13C NMR
spectra for 1 HCl and 4-7, DSC traces for 4 and 7, HPLC/SFC
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chromatograms for 4 and 1 (including chiral stationary phase
traces), 1H NMR for 1 free base, and check for byproduct 8 in 7.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4471