Organic Process Research & Development
ARTICLE
reduction. The use of flow hydrogenation was key for preparing 7
in a rapid manner, which increased both throughput and safety.
the reaction temperature did not rise above 10 °C at any point.
Once dosing was complete, reaction completion was confirmed
with NMR analysis. Excess oxidant was destroyed by addition of
10% aq sodium thiosulfate (600 mL), and the organic layer was
isolated. The organic layer was washed with 1 M HCl (500 mL),
sat. brine (500 mL), and water (500 mL). A 10 mL sample was
taken and concentrated to dryness to get an estimated yield and
an analysis. Based on the results, approximately 170 g (85% yield
over three steps) of aldehyde were formed over the three-step
synthesis. The aldehyde was left in solution in order to do the
final coupling. 1H NMR (400 MHz, CDCl3) 9.78 (s, 1H), 3.41
(t, 2 H), 2.98 (s, 2H), 2.44 (t, 2H), 1.98 (m, 3H), 1.45À1.80
(m, 16 H). 13C NMR (100 MHz, CDCl3) 202.88, 82.11, 71.09,
43.88, 39.89, 37.40, 34.18, 29.18, 28.43, 19.19.
’ EXPERIMENTAL SECTION
General. 1-adamantanemethanol was obtained from Carbo-
synth Ltd. (Berkshire, UK), and deoxynojirimycin was obtained
from Bayer AG (Leverkusen, Germany). Borane/THF complex
(1.0 M) stabilized with N-isopropyl-N-methyl-tert-butylamine
was purchased from Aldrich and used fresh. Due to the weak
absorbing nature of the compound, LC purity determination was
performed using an Agilent 1100 HPLC equipped with a Corona
CAD detector. All reactions were carried out in an inert atmo-
sphere using nitrogen as the blanket gas.
1-Adamantanemethanol Tetrahydropyranyl Ether (2). A
solution of 1-adamantane methanol (1, 132.8 g, 0.8 mol) and
tosic acid (3.04 g, 0.016 mol) in THF (400 mL) was heated to
45 °C under nitrogen. Once at temperature, 3,4-dihydro-2H-
pyran (73.4 mL, 0.8 mol) was added via addition funnel at a rate
such that the temperature was maintained within 0.5 °C of the set
point. Once addition was complete, the reaction was heated to
55 °C for 2 h. The reaction was cooled to rt and sampled for
analysis. The starting material was converted to product in excess
of 95% by NMR analysis and was used for subsequent steps
without further purification. A 2 mL sample was concentrated
under reduced pressure for analysis. 1H NMR (400 MHz,
CDCl3) 4.52 (t, 1H), 3.87 (m, 1H), 3.78 (m, 1H), 3.45 (m,
1H), 3.38 (d, 1H), 2.90 (d, 1H), 1.4À2.0 (m, 20 H). 13C (100
MHz, CDCl3) 98.99, 78.18, 61.75, 39.71, 37.26, 33.72, 30.60,
33.72, 28.31, 25.61, 19.45.
N-[5-(Adamantan-1-yl-methoxy)pentyl]-1-deoxynojirimycin
Methanesulfonic Acid Salt (7). The aldehyde solution from
the previous step was concentrated to a minimum stir volume
(120 mL), and 140 mL of THF and 280 mL of MeOH were
added. In a separate flask, 70 g of deoxynojirimycin (0.428 mol)
were dissolved in 280 mL of DI H2O and added to the aldehyde
solution. The solution was briefly stirred to ensure dissolution
and then polish filtered through a 0.22 μm filter. The reaction
solution was then passed through the H-Cube MIDI flow hydro-
genator at a flow rate of 15 mL/min, over a 20% Pd(OH)2 on a C
catalyst bed, at 145 °C under 95 bar of hydrogen pressure. The
reaction was complete after a single pass through the apparatus.
After hydrogenation, the reaction mixture was charged to a 5 L
three-neck round-bottom flask, equipped with an overhead
stirrer, nitrogen line, and thermocouple. The reaction mixture
was distilled to a minimum stir volume (200 mL), and toluene
(1 L) was charged. The reaction was again distilled to a minimum
stir volume (200 mL). The reaction mixture was dissolved in
1.5 L of 30% methanol in ACN and was brought to rt. Methane-
sulfonic acid (28 mL) was added to the reaction mixture over 1 h.
The reaction mixture was heated to 50 °C and allowed to cool to
rt over 1 h. The reaction was cooled to 0 °C, stirred for 1 h, and
filtered. The filtered solids were suspended in 700 mL of iso-
propanol and dissolved at 50 °C. The reaction was allowed to
cool to rt and stir for 2 h. Filtration followed by drying under
vacuum at 60 °C to a constant weight afforded 130.7 g of the
5-(Adamant-1-yl-methoxy)-1-pentanol (3). The solution of
2 isolated in the previous step was cooled to 5 °C, and 1.6 L of
1 M borane/THF complex in THF (1.6 mol) were slowly added
to the solution via addition funnel over 1 h. Addition was per-
formed slowly in order to prevent any thermal accumulation and
also control the amount of off-gassing observed. Once addi-
tion was complete, the reaction was warmed to rt over 1 h and
then heated at 45 °C for 18 h. The reaction progress was checked
via 1H NMR and was found to be complete. The reaction mixture
was cooled to 5 °C and was quenched by 300 mL of 1 M HCl via
addition funnel over 1 h. Once addition was complete, the re-
action was warmed to 55 °C for 1 h, to ensure destruction of any
borane complexes, and was cooled to rt. The reaction mixture
was diluted with 500 mL of brine, and the organic layer was
isolated. The organic layer was charged to a clean reaction flask,
and 1.8 L of solvent were distilled off. Methylene chloride was
charged to the flask (2 L), and 1 L of solvent was distilled off.
The reaction was filtered to remove a small amount of pre-
cipitated boric acid, and the filtrate was charged to a clean flask
for the subsequent step. A 2 mL sample was taken and
1
desired compound as a white solid (Yield 61.5%). H NMR
(400 MHz, DMSO-d6) 9.26 (s, 1H, from MSA), 5.51 (m, 4H
from OH groups), 3.92 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H),
3.32À2.92 (m, 11H), 2.39 (s, 3H from mesic acid), 1.91 (m, 3H),
1.68À1.30 (m, 18H). 13C NMR (100 MHz, DMSO-d6) δ 81.01,
76.38, 70.38, 67.19, 66.03, 65.36, 53.96, 53.33, 51.99, 39.63
(under DMSO peak, resolves w/APT), 39.23 (under DMSO
peak, resolves with APT), 36.71, 33.60, 38.54, 37.59, 22.92,
21.96. DSC, 182.58 °C, 95.86 J/g (melting point). TGA, 0%
LOD up to 191.3 °C, at which point decomposition occurs.
AUC Purity (HPLC, Corona CAD Detector) 99.4%. This
material contained 740 ppm of residual isopropanol, which
meets ICH guidelines. No other solvents were observed via
GC headspace analysis. Less than 1 ppm of residual Pd was
detected via ICP MS.
1
concentrated under reduced pressure for analysis. H NMR
(400 MHz, CDCl3) 3.63 (t, 2H), 3.40 (t, 2H), 2.95 (s, 2 H), 1.98
(m, 3 H), 1.4À1.8 (m, 19 H). 13C NMR (100 MHz, CDCl3)
81.89, 71.57, 62.77, 39.74, 37.25, 34.09, 32.48, 29.29,
28.30, 22.42.
5-(Adamant-1-yl-methoxy)-1-pentanal (4). The solution of
alcohol 3 from the previous step was cooled to 5 °C, and a solu-
tion of K2CO3 (14.4 g, 0.104 mol), NaHCOs (87.3 g, 1.04 mol),
and KBr (0.95 g, 0.08 mol) in 1.6 L of H2O was charged. TEMPO
(2.5 g, 0.16 mol) was charged to the stirred reaction mixture. The
reaction was then dosed with 10% sodium hypochlorite solution
(600 mL) over 2 h. The reaction was dosed at a rate such that
’ ASSOCIATED CONTENT
Supporting Information. 1H, 13C, APT NMR spectra,
S
b
HPLC data, DSC and TGA data. This material is available free of
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dx.doi.org/10.1021/op2001222 |Org. Process Res. Dev. 2012, 16, 1090–1097