mol) in toluene (5 L) was added to the reaction mixture (a 3
°C exotherm was observed), and the resultant mixture was
stirred for 0.5 h at ambient temperature. The mixture was
separated, and the aqueous phase was washed with dichlo-
romethane (20.7 L). The combined organic phases were washed
with 2 M sodium hydroxide (20.7 L) followed by water (20.7
L). The organic phase was concentrated and replaced with ethyl
acetate (12.4 L) and concentrated to 8 L total volume. The
mixture was cooled, granulated at 0 °C overnight, and filtered,
and the solid was washed with ethyl acetate (4.0 L) and dried
in Vacuo (40 °C) for 12 h to give 1 as a white crystalline solid
(1.08 kg, 37%). Mp 193.5 °C. 1H NMR (400 MHz, CDCl3) δ
[ppm] 7.36 (m, 2), 7.23 (m, 3), 6.61-6.48 (m, br, 1), 5.15 (m,
1), 4.28 (m, 1), 3.36 (d, br, 2), 2.85 (m, 1), 2.48 (s, 3), 2.28 (m,
2), 2.18-1.61 (m, 19), 1.39 (d, 6). 1H NMR (500 MHz, DMSO)
δ [ppm] 8.22 (d, 1), 7.30(m, 4), 7.20 (m, 1), 4.96 (dt, 1), 4.21
(tt, 1), 3.28 (m, 1), 3.27 (m, 1), 3.13 (septet, 1), 2.38 (s, 3),
2.33 (t, 2), 2.32 (m, 1), 2.06-1.63 (m, 4), 2.03-1.82 (m, 2),
2.03-1.76 (m, 2),1.91-1.65 (m, 4), 1.82-1.6 (m, 2), 1.81 (m,
2), 1.74-1.56 (m, 2), 1.24 (d, 6). 13C NMR (125 MHz, DMSO)
δ [ppm] 12.2, 21.7, 24.7, 25.4 (J 13C-19F 9 Hz), 25.6 (J 13C-19F
9 Hz), 25.8, 25.9, 32.1 (J 13C-19F 24, 7 Hz), 32.3 (J 13C-19F
24, 7 Hz), 35.5, 35.8, 40.9, 46.7, 48.0, 50.3, 58.2, 58.4, 123.6,
126.2, 126.4, 128.1, 144.1, 149.6, 158.4, 172.9. FT-IR (cm-1):
3264 (NH, 2° amide); 3062, 3022 (CH, aryl); 2955-2825 (CH,
alkyl); 1662 (CdO, amide); 1531 (NH, amide); 1513, 1494
(CdC, aryl, CdN); 1453 (C-CH3 asymmetric); 1432 (C-CH2,
scissor vibration); 1370 (C-CH3, symmetric); 1290-1195 (CH
in plane deformations, aryl); 1103 (CF); 962 (C-CH3 rock),
754, 702 (CH out of plane deformations, monosubstituted
aromatic). MS m/z 514.4 [M + H]+. Anal. Calcd for
C29H41F2N5O: C, 67.75; H, 8.06; N, 13.54. Found: C, 67.81;
H, 8.04; N, 13.63.
seed the reaction can be cooled to 10 °C to initiate crystalli-
sation), and the mixture was cooled to ambient temperature over
4 h and held for 15 h. The resultant solid was collected by
filtration, washed with methanol (8.6 L), and dried in Vacuo
(40 °C) to give 3 as the L-(+)-tartrate salt (4.16 kg, 33%).
3·L-(+)-tartrate salt (11.1 kg, 33.71 mol) was slurried in
methanol (98.1 L) at ambient temperature. The mixture was
heated to reflux until a solution was obtained, and then it was
cooled to 40 °C over 2 h. A seed was added, and the mixture
cooled to ambient temperature over 4 h and stirred for 15 h.
The reaction was filtered, washed with methanol (10 L), and
dried in vacuo (40 °C) to yield 3·L-(+)-tartrate salt as a white
crystalline solid (6.9 kg, 63%, 95% ee by HPLC). Mp 179.0
1
°C. H NMR (300 MHz, CDCl3) δ [ppm] 7.40-7.25 (m, 5),
4.43 (t, 1), 3.68 (s, 3), 2.66 (d, 2), 1.70 (s, 2). MS m/z 180.3
[M + H]+.
4.5. 3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-
azabicyclo[3.2.1]octane p-Toluenesulfonic Acid Salt (4 ·p-
TsOH). Triazole 9 (600 g, 1.85 mol) and p-toluenesulfonic acid
monohydrate (351 g, 1.85 mol) were dissolved in methanol (3
L), and 10% palladium on carbon (60 g, 10 wt %) was added.
The mixture was stirred under an atmosphere of hydrogen at
50 psi at ambient temperature for 12 h. The reaction mixture
was filtered through Arbocel (filtration aid), and the filter pad
was washed with methanol (500 mL). The methanol was
evaporated under reduced pressure, and the resultant brown oil
was dissolved in hot i-propanol (1.8 L). The solution was
allowed to granulate at room temperature for 12 h and then at
0 °C for 2 h. The white solid was filtered off and dried in Vacuo
(50 °C) for 12 h to give 4 as the tosylate salt (623 g, 83%). Mp
117.0 °C. 1H NMR (300 MHz, CD3OD) δ [ppm] 7.71 (d, 2),
7.23 (d, 2), 4.54 (m, 1), 4.23 (s, br, 2), 3.30-3.25 (m, 1), 2.52
(s, 3), 2.47-2.43 (m, 2), 2.36 (s, 3), 2.22-2.10 (m, 6), 1.34 (d,
6). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (d, J ) 6.84
Hz, 18 H) 2.01 (s, 18 H) 2.28 (s, 15 H) 3.15-3.38 (m, 13 H)
4.23-4.38 (m, 3 H) 7.12 (d, J ) 7.82 Hz, 6 H) 7.50 (d, J )
8.06 Hz, 5 H). 13C NMR (75 MHz, CD3OD) δ [ppm] 11.30,
20.20, 21.07, 25.38, 25.46, 33.25, 46.25, 55.34, 125.74, 128.79,
140.74, 142.33, 151.43, 160.36.
4.6. exo-8-Benzyl-8-azabicyclo[3.2.1]oct-3-ylamine (7). So-
dium metal (24.3 g, 1.06 mol) was added in pieces to toluene
(300 mL) at ambient temperature, and the mixture was heated
to reflux. A solution of 6 (20.0 g, 87 mmol) in toluene (200
mL) and n-pentanol (120 mL) was added slowly over 15 min
to the refluxing reaction when gas evolution was observed. The
resultant mixture was heated at reflux for 2 h to ensure complete
consumption of sodium when a thick white slurry formed. The
reaction was cooled to 80 °C, i-propanol (200 mL) was added,
and the reaction was allowed to cool to ambient temperature
before water (700 mL) was added. Concentrated hydrochloric
acid (140 mL) [exothermic] was added to adjust the aqueous
layer to pH 1. The mixture was stirred for 15 min, and the layers
were separated. Ethyl acetate (700 mL) was added to the
aqueous layer, which was adjusted to pH 12 by the addition of
10 M aqueous sodium hydroxide (40 mL). The layers were
separated, and the organic layer was concentrated under reduced
pressure to yield a pale-yellow oil. n-Pentanol contained in the
oil was removed by azeotropic distillation with water (200 mL)
4.3. 4,4-Difluorocyclohexanecarboxylic Acid (2). The ester
17 (44 g, 0.229 mol) was slurried in methanol (100 mL) and
water (100 mL) at ambient temperature, sodium hydroxide (10.1
g, 0.252 mol) was added and the mixture stirred at ambient
temperature for 15 h. Concentrated hydrochloric acid was added
to adjust the mixture to pH 1, and stirring continued at ambient
temperature for 15 h. The mixture was extracted with dichlo-
romethane (3 × 300 mL). The organic extracts were combined
and concentrated in Vacuo, then purified by chromatography
(90/10 v/v pentane/EtOAc) to yield crude 2 as a crystalline white
solid (23 g). Further purification by two recrystallisations from
hexane, furnished 2 as a crystalline white solid (19 g, 51%).
Mp 105.9 °C. 1H NMR (500 MHz, DMSO-d6) δ ppm
1.54-1.65 (m, 2) 1.88 (s, 6) 2.40 (s, 1). 19F NMR (500 MHz,
CDCl3) δ ppm -101-99 (d, 1) -96-94.2 (d, 1). MS m/z 163
[M - H]-.
19F NMR (300 MHz, CDCl3) δ [ppm] (vinyl fluoride acid)
-102.8 (s, 1).
4.4. Methyl (S)-3-Amino-3-phenylpropanoate (3·L-(+)-
Tartaric Acid). L-(+)-Tartaric acid (5.61 kg, 37.39 mol) in
methanol (43.6 L) was heated to 40 °C. A methanol solution
of 20 (6.7 kg, 37.39 mol in ∼12 L methanol) was added, and
the mixture was heated to reflux until complete solution was
obtained. The resultant solution was cooled to 40 °C over 2 h.
A seed from a laboratory batch was added (in the absence of
1100
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Vol. 12, No. 6, 2008 / Organic Process Research & Development