3.81 (m, 1 H), 3.11-3.06 (m, 1 H), 3.03-2.89 (m, 2 H),
0.92, (d, 3 H, J ) 6.42 Hz) ppm. 13C NMR (DMSO-d6): δ
143.5, 139.8, 135.0, 133.2, 131.2, 130.7, 130.3, 129.2, 128.4,
119.6, 111.0, 68.1, 53.6, 37.2, 22.0. HRMS Calcd for C17H16-
ClNO [M + Ag]: 391.9971. Found: 391.9970.
1
Minor diastereomer: H NMR (DMSO-d6): δ 7.57 (s, 1
H), 7.54 (d, 1 H, J ) 7.23 Hz), 7.41-7.33 (m, 2 H), 7.14
(d, 2 H, J ) 8.43 Hz), 6.97 (d, 2 H, J ) 8.43 Hz), 4.85 (d,
1H, J ) 5.22 Hz), 3.82-3.72 (m, 1 H), 3.32-3.23 (m, 1
H), 2.89-2.78 (m, 2 H), 0.86 (d, 3 H, J ) 6.42 Hz). 13C
NMR (DMSO-d6): δ 144.3, 140.0, 134.3, 132.6, 131.1,
130.6, 130.5, 129.5, 128.4, 119.5, 111.4, 69.5, 55.1, 36.6,
21.9.
Figure 2. Schematic of the experimental setup.
3-[(1S,2R)-1-(4-Chlorobenzyl)-2-methanesulfonylhy-
droxypropyl]benzonitrile. A toluene solution of alcohol 9
(2.85 kg, 9.99 mol) was azeotropically dried and then diluted
to 28.5 L with toluene. The batch was cooled to between
-5 and 0 °C. Triethylamine (1.81 L, 13.0 mol) was added,
followed by slow addition (35 min) of methanesulfonyl
chloride (929 mL, 12.0 mol), maintaining batch temperature
at <20 °C. The batch was aged 10 min, and then 50%
saturated aq NaHCO3 (22.6 L) was added. After separating
the layers, the organic layer was washed with water (14.8
L). The batch was assayed to give 3.53 kg (97% yield) of
mesylate. The batch was azeotropically dried and switched
into DMF in preparation for the mesylate displacement.
Analytical Data for a Chromatographed Sample. 9:1
mixture of diastereomers (m is minor diastereomer, b is both
diastereomers): 1H NMR (CDCl3): δ 7.57-7.52 (m, 1.1 H),
7.47-7.38 (m, 3.2 H), 7.35-7.32 (m, 0.1 H), 7.17 (d, 2 H,
J ) 8.43 Hz), 7.14 (d, 0.2 H, J ) 8.43 Hz), 6.97 (d, 2 H, J
) 8.43 Hz), 6.88 (d, 0.2 H, J ) 8.43 Hz), 5.10-5.04 (m, 1
H), 5.02-4.98 (m, 0.1 H), 3.31 (dd, 0.1 H, J ) 4.82, 13.65
Hz), 3.20 (dd, 1 H, J ) 5.62, 13.65 Hz), 3.20-3.15 (m, 0.1
H), 3.10-3.05 (m, 1 H), 3.02 (s, 0.3 H), 2.97 (dd, 1 H, J )
10.56, 13.65 Hz), 2.91 (s, 3 H), 2.87 (dd, 0.1 H, J ) 10.56,
13.65 Hz), 1.35 (d, 3 H, J ) 6.42 Hz), 1.30 (d, 0.3 H, J )
6.42 Hz). 13C NMR (DMSO-d6): δ 141.1m, 140.9, 138.5b,
135.0, 134.7m, 133.3, 133.0m, 131.2, 131.1m, 131.0, 131.0m,
129.8m, 129.6, 128.5b, 119.3, 119.2m, 111.7m, 111.5,
81.6m, 81.6, 51.7m, 51.4, 38.3, 38.2m, 36.3, 35.7m, 19.9,
19.1m.
3-[(1S,2S)-2-Azido-1-(4-chlorobenzyl)propyl]benzoni-
trile (10). To the DMF solution of mesylate (3.53 kg, 9.70
mol) was added DIEA (2.03 L, 11.64 mol) followed by NaN3
(757 g, 11.64 mol). The reaction temperature was slowly
increased to 70 °C, and the batch was aged for 8-11 h.
Caution! The reaction vessel should be behind a blast
shield due to the use of sodium azide. The batch was cooled
to 25 °C, and 5% aq NaHCO3 (34.4 L) and toluene (13.6 L)
were added. The layers were separated; the organic layer
was washed with water (15.4 L) and then with 1 N HCl (15.4
L) and used directly in the next step (HPLC assay 2.62 kg,
87% yield).
H, J ) 8.03 Hz), 7.48 (d, 1 H, J ) 8.03 Hz), 7.43-7.38 (m,
1.1 H), 7.18 (d, 0.2 H, J ) 8.43 Hz), 7.15 (d, 2 H, J ) 8.43
Hz), 7.08 (d, 0.2 H, J ) 8.43 Hz), 7.00 (d, 2 H, J ) 8.43
Hz), 3.91-3.83 (m, 1.1 H), 3.19 (dd, J ) 4.02, 13.65 Hz),
3.14-3.04 (m, 1.2 H), 2.99-2.90 (m, 1.1 H), 1.15 (d, 0.3
H, J ) 6.42 Hz), 1.04 (d, 3 H, J ) 6.42 Hz). 13C NMR
(DMSO-d6): δ 142.5, 142.1m, 138.9, 138.8m, 134.6m,
134.4, 133.0m, 132.7, 131.3m, 131.2, 131.1, 131.0m, 129.8,
129.6m, 128.5m, 128.5, 119.4m, 119.3, 111.7, 111.5m, 61.3,
60.7m, 52.0, 51.5m, 37.2m, 36.7, 17.8m, 17.3. HRMS Calcd
for C17H15N4Cl [M + Ag]: 417.0036. Found: 417.0038.
Experimental Section for Hydrozoic Acid Assay by FTIR
An FTIR analyzer (ReactIR4000) equipped with an online
gas cell (30 mL) was connected to a 250-mL jacketed resin
kettle. The gas phase during the reaction was examined
continuously by purging dry nitrogen gas through the
headspace at a rate of 16 mL/min. The tubing connecting
the headspace of the reactor to the IR gas-cell was heat-
traced with a set temperature at 68 °C, thus preventing the
condensation of HN3 (bp 37 °C) in the tubing (see Figure 2
for a schematic of the setup).
Reaction Procedures. To a 250-mL, multineck round-
bottom flask equipped with a magnetic stirrer, thermocouple
probe, and nitrogen inlet was charged mesylate (33 mmol)
in DMF (40 mL). NaN3 (39.6 mmol) and/or DIPEA or Na2-
CO3 was added, and the suspension was stirred for 5 min at
room temperature. The mixture was then heated to 80 °C
and stirred until reaction was complete.
Results
The typical absorption bands of HN3 in the vapour of the
reactor are indicated in Figure 3 which includes two spectra,
one of carbon dioxide and the other of hydrazoic acid. Peaks
at 2127 and 2153 cm-1 are the strong absorption bands,
stretches of linear HN3. It is the most visual band used for
tracing the presence of HN3.
DIPEA appears to be an effective reagent to suppress the
appearance of HN3 in the reaction headspace; however, it
could affect the yield if used in large quantity. Therefore,
the amount of DIPEA was reduced to 0.3 equiv to provide
a reasonable yield but still significantly suppress the level
of HN3 in the headspace during the reaction, allowing the
process to be scaled up successfully.
Analytical Data for a Chromatographed Sample of 10.
9:1 mixture of diastereomers (m is minor diastereomer, b is
1
both diastereomers): H NMR (DMSO-d6): δ 7.71 (s, 0.1
H), 7.68 (s, 1 H), 7.59 (d, 1.1 H, J ) 7.63 Hz), 7.53 (d, 0.1
622
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Vol. 11, No. 3, 2007 / Organic Process Research & Development