Practical Synthesis of a γ-Secretase Inhibitor
cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclo-
hexaneacetonitrile (14). L-Selectride (1.0 M in tetrahydrofuran,
100 g, 113 mmol) was cooled to -60 °C. A solution of 4 (40 g,
98 mmol) in THF (200 mL) was added over 90 min, maintaining
the temperature at -60 °C. The solution was aged for 60 min and
then slowly quenched over 60-90 min into a solution of sodium
chloride (30 g) in water (160 mL) containing concd sodium
hydroxide (46 wt % solution; 1.1 g) and 27 wt % aqueous hydrogen
peroxide (50 mL) at -5 °C. A solution of sodium metabisulphite
(11.9 g) in water (100 mL) was added, and the resulting mixture
was allowed to warm to 23 °C. Further sodium metabisulfite
(6.0 g) in water (50 mL) was added and the solution aged for 10
min. The solution was diluted with isopropyl acetate (300 mL) and
the aqueous layer removed. The organic layer was diluted with
isopropyl acetate (254 mL) and washed with water (254 mL). The
organic layer was distilled to a total volume of 150 mL as further
isopropyl acetate (300 mL) was added. The solution was then
reconcentrated to a final volume of 200 mL, and then heptane
(500 mL) was introduced over 30 min. After the solution was cooled
to ambient temperature, the solids were filtered, washed with
heptane (100 mL), and then dried in vacuo at 45 °C to afford the
title compound (38.6 g, 94%): 1H NMR (400 MHz, CD2Cl2) δ
7.44-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.13-7.04 (m, 2H), 6.94-
6.87 (m, 1H), 2.53 (d, J ) 8.0 Hz, 2H), 2.55-2.38 (m, 4H), 2.09-
2.03 (m, 1H), 1.93-1.86 (m, 2H) and 1.71-1.62 (m, 2H); 13C NMR
(100 MHz, CD2Cl2) δ 159.9 (dd, J ) 2.5, 29.3 Hz), 157.5 (dd,
J ) 2.3, 22.9 Hz), 140.8, 133.5, 131.5, 128.9, 118.8, 118.6-118.2
(m, 2C), 117.9 (dd, J ) 10, 23 Hz), 69.9 (d, J ) 4.1 Hz), 30.1,
25.7, 25.7, 20.9; IR ν (cm-1) 1580, 1495, 1304, 1190, 1144, 1082;
mp 161.2-163.2 °C. Anal. Calcd for C20H18ClF2NO2S; C, 58.61;
H, 4.43; N, 3.42. Found: C, 58.61; H, 4.46; N, 3.31.
cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclo-
hexaneacetaldehyde (16). Nitrile 14 (6.00 kg, 13.0 mol) was
slurried in toluene (65.5 kg) and the resulting mixture cooled to
approximately -45 °C. Diisobutylaluminium hydride (1.0 M in
toluene, 15.0 L, 15 mol) was added maintaining the temperature at
-40 °C. The solution was aged for 60 min at -40 °C, and then
MeOH (2.4 L) was added such that the temperature remained below
-35 °C. The resulting solution was allowed to warm to -10 °C
and then added into a citric acid solution (14.4 kg in 66 kg of water).
Toluene (5.3 kg) was used to rinse. The biphasic mixture was
vigorously stirred overnight, and then the layers were separated.
The organic layer was washed with a solution of NaHCO3
(6.35 kg) in water (83 kg) and then with water (59 kg). The toluene
solution was concentrated to approximately 40 L, filtered, and then
diluted to a final volume of approximately 120 L with further
toluene (69.2 kg). The assay yield was 5.13 kg (96%). This solution
was held overnight before concentrating to a final volume of
24.5 L: 1H NMR (400 MHz, CD2Cl2) δ 9.65 (t, 1H, J ) 1.7 Hz),
7.32-7.20 (m, 4H), 6.98-6.88 (m, 2H), 6.85-6.72 (m, 1H), 2.57-
2.45 (dd, J ) 1.7, 7.2 Hz, 2H), 2.45-2.10 (m, 5H) and 1.68-1.35
(m, 4H); 13C NMR (100 MHz, CD2Cl2) δ, 201.6 (d, J ) 7 Hz),
160.0 (d, J ) 47 Hz), 157.5 (d, J ) 39 Hz), 140.7, 133.5, 131.6,
128.9, 118.7 (dd, J ) 4, 25 Hz), 118.3 (dd, J ) 8, 29 Hz), 117.8
(m, 2C), 70.5, 46.5, 26.3, 25.5; IR ν (cm-1) 1716, 1576, 1498,
1476, 1311, 1190, 1142, 1152, 1083; mp 100.0-102.0 °C. Anal.
Calcd for C20H19ClF2O3S; C, 58.18; H, 4.64. Found: C, 58.10; H,
4.63.
(5.13 kg in toluene, total volume 24.5 L) was then added over
20 min maintaining the internal temperature below -20 °C. Further
toluene (1 L) was used to rinse. The mixture was aged for 30 min
at below -20 °C before warming to ambient temperature and
stirring for 2.0 h. Acetic acid (0.35 kg) was added followed by
water (50.3 kg). The layers were separated, and the organic layer
was washed with brine. The volume was reduced to 22 L under
vacuum before DMF (53.5 kg) was added, and the mixture was
reconcentrated under vacuum to a final volume of 61 L. A mixture
of concd HCl (1.22 kg) and water (9.3 kg) was then added, and
the mixture was warmed to 45 °C for 2 h. After cooling, H2O
(25.5 kg) was added to crystallize the product. The solids were
isolated by filtration and washed with a mixture of DMF and water
(4.7 and 5.0 kg, respectively), then water (2 × 15.0 kg). The solids
were then dried in vacuo at 50 °C to give the title compound
(5.6 kg, 87%): 1H NMR (400 MHz, CD2Cl2) δ 9.67 (t, J )
1.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.37-7.33 (m, 2H), 7.13-7.05
(m, 2H), 6.94-6.87 (m, 1H), 2.47 (dt, J ) 1.6, 7.3 Hz, 2H), 2.44-
2.37 (m, 4H) 1.81 (q, J ) 7.4 Hz, 2H), 1.74-1.70 (m, 2H) and
162-1.47 (m, 3H). 13C NMR (100 MHz, CD2Cl2) δ, 202.0 160.0
(dd, J ) 2.4, 52 Hz), 157.5 (dd, J ) 2.4, 45 Hz), 140.6, 133.8,
131.3, 128.7, 122.4 (dd, J ) 7.3, 11 Hz) 118.8 (dd, J ) 4.6,
26 Hz), 118.2 (dd, J ) 8.6, 29 Hz), 117.6 (dd, J ) 10, 24 Hz) 70.8
(d, J ) 4.0 Hz), 42.1, 31.7, 26.0, 25.4 (d, J ) 6.7 Hz), 24.2; IR ν
(cm-1) 1714, 1576, 1496, 1301, 1294, 1190, 1141, 1084; mp
145.9-146.8 °C. Anal. Calcd for C21H21ClF2O3S; C, 59.08; H, 4.96.
Found: C, 59.07; H, 4.91.
cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclo-
hexanepropanoic Acid (1). To a mixture of crude aldehyde 21
(650 g, 1.52 mol) in CH2Cl2 (6 L) and H2O (6 L) was added
sulfamic acid (216 g, 2.21 mol). Sodium chlorite (180 g in 3.13 L
water, 2.0 mol) was added slowly over 30 min maintaining the
internal temperature below 30 °C. The phases were separated, and
the organic layer was washed with an aqueous Na2S2O5 solution
(157 g in 20 L water) and water (20 L) and then dried (Na2SO4).
The solution was concentrated in vacuo and the residue recrystal-
lized from isopropyl acetate/heptane to afford the title compound
1
(482 g, 74%): H NMR (400 MHz, CDCl3) δ 11.1 (br.s, 1H), 7.37-
7.30 (m, 4H), 7.09-6.99 (m, 2H), 6.85-6.79 (m, 1H), 2.39 (br. t,
J ) 7.6 Hz, 6H), 1.85-1.79 (q, J ) 7.5 Hz, 2H), 1.73-1.69 (m,
2H), 1.63-1.58 (m, 1H) and 1.53-1.45 (m, 2H); 13C NMR
(100 MHz, CD2Cl2) δ 179.3 (d, J ) 8 Hz), 160.0 (dd, J ) 2.3, 53
Hz), 157.5 (dd, J ) 2.3, 44 Hz), 140.6, 133.7, 131.5, 128.8, 122.2
(m, 1C), 118.7 (dd, J ) 4.5, 26 Hz), 118.2 (dd, J ) 8.5, 29 Hz),
117.7 (dd, J ) 10, 24 Hz), 70.8 (d, J ) 4.1 Hz), 32.1, 31.6, 26.8,
25.9, 25.4 (d, J ) 6.4 Hz); IR ν (cm-1) 2935, 2873, 1692, 1583,
1495, 1476, 1306, 1277, 1193, 1139, 1082; mp 166.6-167.5 °C.
Anal. Calcd C21H21ClF2O4S; C, 56.95; H, 4.78. Found: C, 56.97;
H, 4.74.
Acknowledgment. We thank Derek J. Kennedy and Robert
A. Reamer for NMR support, Jennifer Chilenski for determining
the single-crystal X-ray structures, Mirlinda Biba for assay
method development, and Alexia Bertrand for IR spectra
determination.
Supporting Information Available: Copies of 1H and 13C NMR
spectra for all new compounds. ORTEP plots and CIF files for 5
and 6. Experimental procedures and characterization data for 2, 8,
10, and 12. This material is available free of charge via the Internet
cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclo-
hexanepropanal (21). Methoxymethyltriphenylphosphonium
chloride (6.6 kg, 19.3 mol) was slurried in THF (29.7 kg) and cooled
to -60 °C. KO-t-Bu (16.2 kg, 18.0 mol) was then added such that
the internal temperature did not exceed -30 °C. Aldehyde 16
JO070407N
J. Org. Chem, Vol. 72, No. 11, 2007 4155