Synthesis of a γ-Secretase Inhibitor
17.0 Hz, 1H), 5.20 (dq, J ) 1.4, 10.2 Hz, 1H), 4.91 (t, J ) 4.4 Hz,
1H), 3.93 (m, 4H), 3.30 (m, 1H), 3.12 (m, 1H), 2.51 (m, 2H), 2.02
(m, 1H), 1.58 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4 (dd,
J ) 2.0, 243.5 Hz), 158.1 (dd, J ) 2.6, 249.0 Hz), 138.9 (m), 135.5
(q, J ) 33.2 Hz), 131.8, 130.9, 125.5 (q, J ) 3.6 Hz), 123.0 (dd,
J ) 7.2, 11.6 Hz), 123.0 (q, J ) 273.1 Hz), 119.9, 118.7 (dd, J )
4.2, 25.8 Hz), 118.1 (dd, J ) 8.6, 29.2 Hz), 118.0 (dd, J ) 10.0,
23.8 Hz), 103.6, 71.9 (dd, J ) 1.2, 4.6 Hz), 65.0 (d, J ) 6.2 Hz),
36.2 (d, J ) 6.6 Hz), 28.1, 25.5 (d, J ) 5.6 Hz); mp 93-94 °C;
Anal. Calcd for C22H21F504S: C, 55.46; H, 4.44. Found: C, 55.31;
H, 4.38.
(m, 1H), 7.45-7.42 (m, 2H), 7.25-6.95 (m, 3H), 5.89 (s, 1H),
3.75-3.52 (m, 2H), 3.49-3.42 (m, 1H), 2.85-2.80 (m, 1H), 2.58-
2.45 (m, 1H), 2.40-2.30 (m, 2H), 2.08-1.98 (m, 1H), 1.73-1.53
(m, 2H); 13C NMR (100 MHz, DMSO-d6, 70 °C) δ 168.7, 165.5,
159.0 (d, J ) 250.0 Hz), 158.5 (d, J ) 241.2 Hz), 139.7, 134.3 (q,
J ) 32.0 Hz), 133.4, 131.3, 130.6, 129.6, 128.8, 126.4 (q, J )
3.6), 123.7 (q, J ) 273), 121.2 (m), 118.9 (3C, m), 72.7, 72.2 (m),
62.6, 46.0, 39.2, 27.6, 26.4, 24.0; mp 167-168 °C; [R]20 +5.35
D
(c 1.0, MeOH, >99% ee); enantiopurity was determined via
supercritical fluid chromatography (Chiralpak AD, 0.7 mL/min, 150
bar CO2, t ) 0 min @ 11% MeOH, t ) 12 f 20 min @ 17%
MeOH, tR ) 11.0-11.7 and 12.1-12.7 min) following acetylation
(MTBE/NaOH, concentrate MTBE extract, and dissolve in MeOH/
Ac2O).
cis-5-(2,5-Difluorophenyl)-5-{[4-(trifluoromethyl)phenyl]sul-
fonyl}-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazole (3). Dioxolane
5 (28.0 kg, 58.8 mol) and hydroxylamine hydrochloride (5.31 kg,
76.0 mol) in a mixture of ethanol (140 L) and water (28 L) were
aged at 70 °C for 2 h and then cooled to 50 °C. A solution of
chloramine-T hydrate (20.1 kg, 88.2 mol) in a mixture of water
(56 L) and ethanol (196 L) was then added, and the mixture was
aged at 50 °C for 2 h before cooling to ambient temperature. The
resultant slurry was filtered, and the solid was washed with a 4:1
mixture of EtOH/H2O (20 L). Drying in vacuo furnished the title
N-((1R,2S,4S)-2-Bromomethyl-4-(2,5-difluorophenyl)-4-{[4-
(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfon-
amide (16). To a slurry of ((1R,2S,5R)-2-amino-5-(2,5-difluorophe-
nyl)-5-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol D-
dibenzoyl hemitartrate (4.10 kg, 3.3 mol) in CH2Cl2 (76.0 kg) was
added 0.4 N NaOH (23.5 kg, 9.4 mol), and the resultant mixture
was aged for 45 min. The lower organic layer was separated, washed
with water (13 kg), and then reduced in volume to 12 L by
distillation at atmospheric pressure. Triethylamine (1.67 kg, 16.5
mol) was added, followed by a solution of methanesulfonic
anhydride (2.83 kg, 16.3 mol) in methylene chloride (11 kg) while
maintaining T < 10 °C. DMF (30 kg) was then added, and the
mixture was distilled to remove the CH2Cl2 and to reach a volume
of 34 L. Sodium bromide (1.34 kg, mol) was added, and the batch
was heated to 85 °C for 7 h. DMF (7 kg) was added, followed by
water (35 L), to crystallize the product. The resultant slurry was
filtered, and the solid was washed with water (2 × 5 L). Drying in
vacuo furnished the title compound as an off-white solid (3.49 kg,
1
compound as a tan solid (21.4 kg, 84%). H NMR (600.1 MHz,
DMF-d7, 350 K) δ 7.97 (d, J ) 8.3 Hz, 2H), 7.77 (d, J ) 8.3 Hz,
2H), 7.38-7.34 (om, 2H), 7.19 (m, 1H), 4.50 (dd, J ) 10.2, 7.9
Hz, 1H), 3.88 (dd, J ) 10.2, 7.9, 1H), 3.33 (ddd, J ) 13.2, 5.3, 3.4
Hz, 1H), 3.30-3.17 (om, 2H), 2.85 (m, 1H), 2.25-2.18 (om, 2H),
2.13 (td, J ) 12.8, 1.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 159.0 (dd, J ) 2.0, 249.3 Hz), 158.7 (dd, J ) 2.5, 241.7 Hz),
157.4, 139.0, 134.8 (q, J ) 32.4 Hz), 131.5, 126.5 (q, J ) 3.6 Hz),
123.6 (q, J ) 273.2 Hz), 119.9 (dd, J ) 7.8, 11.4 Hz), 119.3 (3C,
m), 72.9, 71.0 (m), 45.2, 35.1 (d, J ) 6.4 Hz), 30.4 (d, J ) 7.0
Hz), 21.3; mp 212-214 °C; Anal. Calcd for C20H16F5N03S: C,
53.93; H, 3.62; N, 3.14. Found: C, 53.68; H, 3.60; N, 3.04.
((1R,2S,5R)- and ((1S,2R,5S)-2-Amino-5-(2,5-difluorophenyl)-
5-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol (2).
Isoxazoline 3 (50.0 g, 112 mmol) was slurried in tetrahydrofuran
(300 mL) and cooled to -5 °C. Diisobutylaluminum hydride (20
% w/t in toluene, 212 mL, 252 mmol) was added while maintaining
T < -3 °C. The resultant solution was aged for 1.5 h, warmed to
50 °C for 1.5 h, and then recooled to 0 °C. Methanol (10 mL) was
added while maintaining T < 15 °C, and then aqueous sodium
hydroxide (2 M, 300 mL) was added. The mixture was stirred for
14 h, and then the layers were separated. The organic layer was
distilled to a volume of 250 mL while toluene (250 mL) was added.
The mixture was allowed to cool. The resultant slurry was filtered,
and the solids were washed with toluene (50 mL). Drying in vacuo
1
91%, >99% ee). H NMR (400 MHz, DMSO-d6, 80 °C) δ 7.89
(d, J ) 8.4 Hz, 2H), 7.67 (d, J ) 8.4 Hz, 2H), 7.28 (m, 1H), 7.15
(d, J ) 7.3 Hz, 1H), 7.10 (m, 2H), 3.68 (m, 1H), 3.62 (dd, J ) 6.6,
10.1 Hz, 1H), 3.52 (br t, J ) 8.2 Hz, 1H), 2.97 (s, 3H), 2.79 (br m,
1H), 2.60 (br m, 1H), 2.45 (m, 1H), 2.22 (t, J ) 13.5 Hz, 1H),
2.03 (m, 1H), 1.82 (m, 1H), 1.43 (m, 1H);13C NMR (100 MHz,
DMF-d7, 5 °C) δ 158.9 (dd, J ) 2.8, 247.5 Hz), 158.6 (dd, J )
2.0, 239.5 Hz), 138.9 (m), 134.5 (q, J ) 33.0 Hz), 131.5, 126.3
(m), 123.6 (q, J ) 273.1), 120.7 (m), 118.9 (3C, m), 70.9 (d, J )
3.9 Hz), 49.9, 40.6, 39.7, 35.4, 28.6 (m), 24.2, 23.9 (m); mp 200-
201 °C; [R]20 -26.9 (c 1.0, MeOH, >99% ee); Anal. Calcd for
D
C21H21BrF5N04S2: C, 42.72; H, 3.59; N, 2.37. Found: C, 42.81;
H, 3.55; N, 2.24. The separation of the enantiomers was ac-
complished by HPLC analysis (Chiralpak AD, 2.0 mL/min, 90%
hexane, 10% EtOH, tR ) 13.2, 17.9 min).
1
furnished the title compound as a white solid (40.9 g, 82%). H
NMR (400 MHz, DMSO-d6, 80 °C) δ 7.88 (d, J ) 8.3 Hz, 2H),
7.67 (d, J ) 8.3 Hz, 2H), 7.26 (m, 1H), 7.08 (m, 2H), 3.40 (m,
2H), 3.08 (m, 1H), 2.47 (m, 2H), 2.40 (d, J ) 12.8 Hz, 1H), 2.25
(t, J ) 12.8 Hz, 1H), 1.69 (m, 1H), 1.36 (m, 2H); 13C NMR (100
MHz, DMSO-d6) δ 158.9 (dd, J ) 2.8, 248.1 Hz), 158.5 (dd, J )
2.1, 241.3 Hz), 139.8, 134.3 (q, J ) 32.4 Hz), 131.3, 126.3 (q, J )
3.8 Hz), 123.7 (q, J ) 272.9 Hz), 121.9 (dd, J ) 7.2, 12.4 Hz),
119.2 (dd, J ) 4.6, 25.8 Hz), 118.9 (dd, J ) 9.0, 29.2 Hz), 118.5
(dd, J ) 10.0, 23.8 Hz), 72.6 (m), 63.7, 45.2, 40.7, 30.6, 26.1 (m),
23.7 (d, J ) 7.4 Hz); mp 212-214 °C; Anal. Calcd for C20H20F5-
N03S: C, 53.45; H, 4.49; N, 3.12. Found: C, 53.24; H, 4.41; N,
2.99.
((1S,2R,5S)-2-Amino-5-(2,5-difluorophenyl)-5-{[4-(tri-
fluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol D-Dibenzoyl
Hemitartrate. To a solution of rac-2 (7.5 kg, 16.7 mol) in THF
(56.3 L) was added a solution of dibenzoyl-D-tartaric acid (2.99
kg, 8.34 mol) in IPAc (56.3 L) while maintaining T < 25 °C. The
resultant mixture was aged overnight and filtered, and the solids
were washed with THF/IPAc (1:1, 22.5 L), followed by THF (22.5
L). Drying in vacuo furnished the title compound as a white solid
(4.05 kg, 39%, 96% ee). 1H NMR (400 MHz, MeOH-d4) δ 8.18-
8.13 (m, 2H), 7.83-7.80 (m, 2H), 7.63-7.60 (m, 2H), 7.59-7.51
(4aS,6S,8aR)-6-(2,5-Difluorophenyl)-1-(4-methoxybenzyl)-6-
{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-ben-
zothiazine 2,2-Dioxide (22). THF (14.7 kg) was cooled to less than
-60 °C, and hexyllithium (5.2 kg of a 2.28 M solution in hexane,
16.8 mol) was added at T < -20 °C. Diisopropylamine (1.78 kg,
17.6 mol) was then added while maintaining T < -20 °C. The
resultant solution was cooled to -60 °C, and then a solution of 16
(3.22 kg, 5.45 mol) in THF (4.8 kg) was added while maintaining
T < -45 °C. The resultant solution was aged for 3 h, and then
water (0.11 kg, 6.15 mol) was added while maintaining T < -40
°C. The solution was allowed to warm to -20 °C, and a solution
of NaI (0.42 kg, 2.80 mol) in DMAc (8.66 kg) was added, followed
by para-methoxybenzyl chloride (1.58 kg, 10.1 mol). The mixture
was warmed to room temperature and aged to reach full conversion.
A solution of HCl [1.64 L of concentrated HCl (specific gravity
1.18) diluted with 17 L of water, 19.4 mol] was added while
maintaining T < 50 °C. Toluene (44.3 kg) was added, and the layers
were separated. The organic layer was washed with water (3 ×
8.9 kg) and then distilled to reach a volume of 22.5 L, adding
toluene as necessary to reach a residual THF content of <2 mol %
(1H NMR). Heptane (12.6 kg) was added, and the resultant slurry
was filtered and washed with a 1:1 mixture of toluene and heptane
J. Org. Chem, Vol. 71, No. 8, 2006 3091