Organic Process Research & Development
Article
cooled to 0 °C, and 1 M borane−THF (25.6 L, 25.6 mol) was
added during 2 h, maintaining a reaction temperature below 2
°C. The reaction was initially warmed to 15 °C to ensure no
exothermic reaction would occur and was then stirred at 50 °C
for 16 h. When HPLC analysis indicated that less than 8% of 6
remained, the reaction mixture was quenched into 4 M KOH
(8 L), maintaining a temperature below 30 °C. The organic
layer was concentrated under reduced pressure, and the
aqueous layer was extracted twice with MTBE (2 × 10 L).
The combined MTBE extract was added to the concentrated
organic layer, and the combined organic layers were then
charged to a solution of 6 M HCl (10 L), maintaining a
temperature below 30 °C. The aqueous phase was washed with
MTBE (10 L) and then basified with 6 M KOH (12 L). The
aqueous phase was extracted twice with THF (10 L and then 5
L), and the combined organic phase was concentrated under
reduced pressure. Toluene (5 L) was added and then azeotrope
distilled off to remove any residual water. The mixture was
triturated with toluene (5 L), and the solids were filtered off
and washed with toluene (3 L). The filtrate was concentrated
under reduced pressure, affording 4 as the free amine (1.13 kg,
71 wt %, 70% yield). 1H NMR (CDCl3, 270 MHz) δ 7.12−7.00
(4H, m), 2.72−2.59 (4H, m), 2.52 (2H, d), 2.27 (3H, s), 1.64
(1H, m), 1.48−1.25 (4H, br s); 13C NMR (CDCl3, 67.5 MHz)
δ 139.0, 136.3, 130.5, 129.9, 126.2, 125.9, 44.7 (2C), 43.8, 34.3,
19.6; HRMS (ESI): [M + H]+ m/z alcd for C11H18N2,
179.1548; found, 179.1553
2-(2-Methylbenzyl)propane-1,3-diamine (4) L-Tartrate
Salt. Crude diamine 4 (2.28 kg, 71 wt %, 9.1 mol) was added
to ethanol (4 L). A solution of L-tartaric acid (1.62 kg, 10.8
mol) in ethanol (11 L) was added, keeping the temperature
below 40 °C. The mixture was stirred for 16 h at 25 °C, and
then the solids were filtered off, washed with ethanol (2 × 2 L),
and dried under reduced pressure 50 °C to give the L-tartrate
salt of 4 (3.21 kg, 94 wt %, quantitative yield). 1H NMR (D2O,
270 MHz) δ 7.30−7.15 (4H, m), 4.27 (2H, s), 3.20−3.07 (2H,
dd), 3.04−2.94 (2H, dd), 2.79 (2H, d), 2.41 (1H, m), 2.27
(3H, s); 13C NMR (D2O, 67.5 MHz) δ 178.4 (2C), 137.2,
135.7, 131.0, 130.0, 127.6, 126.7, 73.9 (2C), 40.5 (2C), 35.9,
32.8, 18.7; HRMS (ESI): [M + H]+ m/z calcd for C11H18N2,
179.1548; found, 179.1553
filtered off, washed with CH3CN (2 × 5 L), and dried under
reduced pressure at 40 °C to afford 2.94 kg of 1-(R) D-tartrate
salt (95 wt %, 62% yield from 4, 88% ee). 1H NMR (DMSO-d6,
270 MHz) δ 7.50 (1H, t), 7.22−7.05 (4H, m), 5.98−5.85 (1H,
m), 5.35−5.12 (2H, m), 4.48 (2H, d), 3.95 (2H, s), 3.13−2.99
(2H, m), 2.90−2.79 (1H, m), 2.75−2.58 (2H, m), 2.26 (3H, s),
2.08 (1H, m); 13C NMR (DMSO-d6, 67.5 MHz) δ 174.6 (2C),
156.6, 137.4, 136.1, 133.7, 130.3, 129.7, 126.3, 125.8, 117.0,
71.8 (2C), 64.4, 65.5, 37.6, 32.7, 19.1, 18.9; HRMS (ESI): [M +
H]+ m/z calcd for C15H22N2O2, 263.1760; found, 263.1769
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank our separation science laboratory group for
determination of enantiomeric purities and our analytical
specialists for recording analytical data such as HRMS and
HPLC analyses. We also thank Drs. Thomas Antonsson and
Magnus Polla for linguistic advice on this manuscript.
REFERENCES
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(R)-Allyl (3-Amino-2-(2-methylbenzyl)propyl)-
carbamate (1-(R)) D-Tartrate Salt. A reactor was charged
with 2-(2-methylbenzyl)propane-1,3-diamine (4) L-tartrate salt
(3.79 kg, 94 wt %, 10.9 mol) and water (17 L). 10 M NaOH
(17 L, 170 mol) was added, maintaining a reaction temperature
below 25 °C. The mixture was stirred for 30 min at 25 °C, and
then 2-MeTHF (14 L) was added. The layers were separated,
and the aqueous phase was extracted with 2-MeTHF (14 L).
The combined organic phase was dried (sodium sulfate),
filtered, and concentrated under reduced pressure, affording the
free diamine 4. A reactor was charged with 4, 2-MeTHF (37.4
L), and diallyl carbonate (1.80 kg, 12.6 mol). Immobilized
lipase Amano PS IM (5.61 kg, 3 wt equivalents) was added in
portions over 30 min, and the temperature was set at 30 °C.
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After 4 days, H NMR indicated less than 5% starting material
left, and the reaction mixture was filtered through Celite and
concentrated under reduced pressure to afford 1-(R) (2.68 kg,
82% ee). To the crude (R)-allyl (3-amino-2-(2-methylbenzyl)-
propyl)carbamate (1-(R); 2.68 kg) was added EtOH (7.1 L). A
solution of D-tartaric acid (1.53 kg, 10.2 mol) in EtOH (8 L)
was added, keeping the temperature below 25 °C. After 16 h at
25 °C, acetonitrile CH3CN (5 L) was added. The solids were
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX