Chung et al.
10 (4.88 kg, 18.46 mol) in heptane (∼65 L total) from the
previous step was solvent-switched to an ethanolic solution
(∼20.6 L total). To the solution was added 50% NaOH (2.7 L,
51.15 mol) over 2 min with stirring. The mixture, which
exothermed from 16 to 34 °C, was heated to reflux at 78-80
°C under nitrogen for 5 h (or until product >95 A%). The
reaction was monitored by HPLC Condition C: tR for trans-
pyrrolidine amide, 10.48 min; cis-pyrrolidine acid, 11.26 min;
cis-pyrrolidine amide, 11.81 min; trans-pyrrolidine acid, 12.80
min; trans- & cis-pyrrolidine nitrile, 13.05 min; alpha ethylated
pyrrolidine nitrile, 18.10 min; C-phosphate pyrrolidine nitrile,
18.91 min. Both starting material and the intermediate amides
were <0.8 A% at end of 5 h reflux. Significant ammonia gas
was released during the reaction. After cooling to 20 °C, the
solution was diluted with ethanol (25.4 L) and methanol (40.6
L) to give a total volume of ∼88 L. The solution was cooled to
12 °C then adjusted to apparent pH 6.5 with 96% H2SO4 (1.42
L, 51.15 mol), while maintaining the temperature at ∼20 °C.
The resulting slurry was filtered through a bed of Solka-floc
(5 kg) and anhydrous powder Na2SO4 (4 kg), and washed with
1:1 EtOH:MeOH (20 L). The filtrate was re-filtered (5 µm
filter), concentrated and solvent-switched to a 2-propanol
solution (∼15 L). The product crystallized during solvent
switch, and the batch was then heated to reflux at ∼80 °C for
2 h which only partially dissolved product. After cooling to 16
°C, MTBE (30.4 L, 3 vol relative to IPA) was slowly added to
the mixture over 5 h. After stirring at 16-17 °C for 3 days,
the slurry was filtered and washed with 12 L 1:3 IPA:MTBE.
After vacuum (150 Torr) drying at 50 °C afforded 5.09 kg of 5
as a white crystalline solid. The yield was 95% for the step
(87% overall for the 2-step). Product loss to the ML/washes
were 160 g (3%). 1: purity, 99.97 LCAP (Condition B),
>99.99% ee (Condition E). mp (DSC): onset 215 °C, peak 217
(1S)-2-Bromo-1-(4-methoxyphenyl)ethanol (23).22 Pre-
pared from 2-bromo-1-(4-methoxyphenyl)-ethanone using ex-
perimental procedure as described for 5, except the substrate
was added as a THF solution. The chiral assay (HPLC
Condition K) of crude 26 was 91% ee 1H NMR (CDCl3) δ 7.28
(d, J ) 8.6, 2H), 6.89 (d, J ) 8.7, 2H), 4.84 (m, 1H), 3.80 (s,
3H), 3.45-3.62 (om, 2H), 2.98 (bs, 1H); 13C NMR (CDCl3) δ
159.4, 132.5, 127.1 (2C), 113.9 (2C), 73.2, 55.1, 38.8.
(1S)-2-(tert-Butylamino)-1-(4-methoxyphenyl)etha-
nol (26). Prepared from 4′-methoxy-2-bromo acetophenone
using experimental procedure as described for 3. The chiral
assay (HPLC Condition F) of isolated 26 was 99% ee (retention
time: S-isomer, 5.0 min; R-isomer, 5.7 min). mp (DSC): onset
110.12 °C, end 114.32 °C, peak 112.90 °C; 1H NMR (CDCl3) δ
7.30 (d, J ) 8.7, 2H), 6.89 (d, J ) 8.7, 2H), 4.55 (dd, J ) 8.9,
3.6, 1H), 3.81 (s, 3H), 2.85 (dd, J ) 11.7, 3.7, 1H), 2.59 (dd, J
) 11.7, 8.8, 2H), 1.10 (s, 9H); 13C NMR (CDCl3) δ 159.0, 135.0,
127.0 (2C), 113.7 (2C), 72.1, 55.3, 50.3, 50.2, 29.2 (3C). Anal.
Calcd for C12H19NO: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.53; H, 9.78; N, 6.11.
3-{tert-Butyl[(2S)-2-hydroxy-2-phenylethyl]amino}-
propanenitrile (28). Prepared from amino-alcohol 24 using
experimental procedure as described for 8. The chiral assay
(HPLC Condition G) of isolated 28 was >99.5% ee (retention
time: S-isomer, 7.2 min; R-isomer, 8.4 min). 1H NMR (CDCl3)
δ 7.38 (m, 4H), 7.36 (m, 1H), 4.57 (dd, J ) 10.2, 3.7, 1H), 3.70
(bs, -OH), 2.99 (m, 1H), 2.86 (m, 1H), 2.75 (dd, J ) 13.9, 3.7,
1H), 2.60-2.40 (m, 3H), 1.15 (s, 9H); 13C NMR (CDCl3) δ 142.4,
128.4, 127.6, 125.8, 118.8, 71.3, 59.7, 55.7, 47.4, 27.3, 20.2;
HRMS m/z [M + H]+ calcd for C15H23N2O, 247.1810; found,
247.1805.
3-{tert-Butyl[(2S)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-
amino}propanenitrile (29). Prepared from amino-alcohol 26
using experimental procedure as described for 8. The chiral
assay (HPLC Condition G) of isolated 28 was 98% ee (retention
time: R-isomer, 9.2 min; S-isomer, 10.2 min). 1H NMR (CDCl3)
δ 7.27 (d, J ) 8.7, 2H), 6.87 (d, J ) 8.7, 2H), 4.50 (dd, J )
10.1, 3.7, 1H), 3.77 (s, 3H), 3.66 (bs, -OH), 2.96 (m, 1H), 2.83
(m, 1H), 2.68 (dd, J ) 13.9, 3.7, 1H), 2.55-2.40 (m, 3H), 1.12
(s, 9H); 13C NMR (CDCl3) δ 159.1, 134.5, 127.0, 118.8, 113.8,
71.0, 59.7, 55.6, 55.2, 47.4, 27.3, 20.2; HRMS m/z [M + H]+
calcd for C16H25N2O2, 277.1916; found, 277.1909.
1
°C; H NMR (D2O) δ 7.30 (m, 1H), 6.92-6.85 (om, 2H), 4.68
(OH), 3.75-3.66 (om, 3H), 3.45 (bm, 1H), 3.30-3.14 (om, 2H),
1.32 (s, 9H); 13C NMR (D2O) δ 176.5, 162.8 (dd, J ) 123.7,
12.6), 160.3 (dd, J ) 124.5, 12.7), 129.9 (dd, J ) 10.1, 5.9),
119.7, 111.7 (dd, J ) 21.5, 3.6), 104.1 (t, J ) 26.2), 62.0, 51.9,
51.0, 50.6, 41.3, 23.7 (3C); [R]40525 -161.8 (c 0.1, MeOH). Anal.
Calcd for C15H19F2NO2: C, 63.59; H, 6.76; F, 13.41; N, 4.94.
Found: C, 63.50; H, 6.81; F, 13.11; N, 4.91.
(3S,4R)-1-tert-Butyl-4-(2,4-difluorophenyl)pyrrolidine-
3-carboxamide (19t). An analytical sample of the trans
amide was prepared from acid 1, via the acyl imidazole and
quenching with ammonium hydroxide: 1H NMR (CDCl3) δ 7.28
(m, 1H), 6.84-6.73 (om, 2H), 6.60 (br s, 1H), 5.92 (br s, 1H),
3.67 (m, 1H), 3.26 (t, J ) 8.7, 1H), 3.08 (dd, J ) 9.2, 4.2, 1H),
2.98 (t, J ) 8.3, 1H), 2.87 (m, 1H), 2.61 (t, J 8.5, 1H), 1.11 (s,
9H); 13C NMR (CDCl3) δ 177.8, 161.7 (dd, J ) 248.4, 12.9),
160.7 (dd, J ) 248.6, 12.0), 129.8 (dd, J ) 9.4, 6.4), 126.1 (dd,
J ) 14.1, 3.6), 111.4 (dd, J ) 20.9, 3.6), 104.0 (q, J ) 51.8),
53.2, 52.4, 51.2, 50.4, 41.5, 26.1 (3C). Anal. Calcd for
C15H20F2N2O: C, 63.81; H, 7.14; N, 9.92; F, 13.46; O 5.67.
Found: C, 63.72; H, 7.00; N, 9.89, F, 13.91.
(1S)-2-Chloro-1-phenylethanol (21). Prepared from 2-
chloro-1-phenylethanone using experimental procedure as
described for 5. The chiral assay (HPLC Condition J) of crude
21 was 99.8% ee (retention time: S-isomer, 13.4 min; R-isomer,
15.0 min). The spectroscopic data are consistent with the
literatures.22
(1S)-2-(tert-Butylamino)-1-phenylethanol (24). Pre-
pared from chloro-alcohol 21 using experimental procedure as
described for 3. The chiral assay (HPLC Condition F) of
isolated 24 was >99.5% ee (retention time: S-isomer, 4.0 min;
R-isomer, 4.7 min). mp (DSC): onset 106.51 °C, end 108.59
°C, peak 107.82 °C; 1H NMR (CDCl3) δ 7.24-7.40 (m, 5H), 4.61
(dd, J ) 8.8, 3.7, 1H), 2.88 (dd, J ) 11.9, 3.7, 1H), 2.62 (dd, J
) 11.8, 8.8, 1H), 1.11 (s, 9H); 13C NMR (CDCl3) δ 143.0, 128.3
(2C), 127.4, 125.8 (2C), 72.4, 50.32, 50.27, 29.2 (3C). Anal.
Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.25. Found: C,
74.67; H, 10.17; N, 7.20.
(3S,4R)-1-tert-Butyl-4-phenylpyrrolidine-3-carbo-
nitrile (30). Prepared from alcohol-nitrile 28 using experi-
mental procedure as described for 10. After workup the crude
1
material was used as is in the next step. H NMR (CDCl3) δ
7.37-7.33 (m, 4H), 7.29 (m, 1H), 3.52 (dd, J ) 15.8, 8.1, 1H),
3.32 (t, J ) 12.2 Hz, 1H), 3.23 (t, J ) 9.0, 1H), 3.00-3.10 (m,
2H), 2.91 (t, J ) 8.3, 1H), 1.15 (s, 9H); 13C NMR (CDCl3) δ
140.8, 129.0, 127.6, 127.2, 121.0, 53.3 (2), 50.7, 48.9, 36.1, 25.9;
HRMS m/z [M+H]+ calcd for C15H20N2, 229.1705; found,
229.1704.
(3S,4R)-1-tert-Butyl-4-(4-methoxyphenyl)pyrrolidine-
3-carbonitrile (31). Prepared from alcohol-nitrile 29 using
experimental procedure as described for 10. After workup the
crude material was used as is in the next step. 1H NMR
(CDCl3) δ 7.25 (d, J ) 8.7 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H),
3.81 (s, 3H), 3.46 (dd, J ) 15.9, 8.0, 1H), 3.25 (t, J ) 8.3, 1H),
3.17 (t, J ) 8.8, 1H), 3.01 (t, J ) 8.3, 1H), 2.94 (AB q, J )
16.1, 8.0, 1H), 2.81 (AB q, J ) 9.2, 7.4, 1H), 1.12 (s, 9H); 13C
NMR (CDCl3) δ 159.1, 133.3, 128.3, 121.5, 114.4, 55.5, 53.6,
52.7, 50.8, 48.4, 36.5, 26.1; HRMS m/ z [M+H]+ calcd for
C16H23N2O, 259.1810; found, 259.1803.
(3S,4R)-1-tert-Butyl-4-(4-methoxyphenyl)pyrrolidine-
3-carboxylic acid (33). Prepared from pyrrolidine-nitrile 31
using experimental procedure as described for 1. The chiral
assays (HPLC Condition H) of crude and isolated 33 were 95%
ee and >99% ee respectively (retention time: 3S,4R-isomer,
1
18.8 min; 3R,4S-isomer, 19.4 min). H NMR (CD3OD) δ 7.31
(d, J ) 8.7, 2H), 6.88 (d, J ) 8.7, 2H), 4.89 (OH), 3.79-3.68
(om, 3H), 3.76 (s, 3H), 3.55 (br t, J ) 10.6, 1H), 3.25 (br t, J )
11.2, 1H), 3.11 (AB q, J ) 18.8, 10.0, 1H), 1.41 (s, 9H); 13C
3600 J. Org. Chem., Vol. 70, No. 9, 2005