L. Lang et al. / Bioorg. Med. Chem. 14 (2006) 3737–3748
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3.9. trans- and cis-Pentamethylbenzyl 4-(4-nitro-
benzenesulfonyl)-oxycyclohexanecarboxylates (23, 24)
32.6, 35.1, 39.1, 42.0, 62.8, 80.1, 129.2, 133.1, 134.0,
136.3, 174.2. MS (EI) 382 (M+), 338, 308, 286, 256,
205, 175, 160, 145, 131, 108, 81.
To a solution of 0.61 g (2.0 mmol) mixture of 19 and 20
obtained from the mother liquor as described earlier in
10 ml methylene chloride were added 4-nitro-
benzenesulfonyl chloride (0.44 g, 2.0 mmol) and triethyl-
amine (0.28 ml, 2.0 mmol). The mixture was stirred at
room temperature overnight. At the end of the reaction,
the solid was filtered and the solution was loaded on a
5.5 · 20 cm silica gel and eluted with 20% ethyl ace-
tate/hexane to give 0.41 g 23 (42%) and 0.15 g of 24
(16%) as a white solid.
3.12. cis-4-Fluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-
yl]ethyl}-N-(2- pyridyl)cyclohexanecarboxamide (12)
To a 5 ml V-vial were added 150 mg of 15, 0.3 ml ani-
sole, and 2 ml of trifluoroacetic acid. The mixture was
stirred at room temperature for 5 min. Trifluoroacetic
acid was evaporated and 0.20 ml of dichloromethyl
methylether was added and heated at 90 C for 5 min.
The vial was cooled and evaporated with argon flow.
To the above residue, 0.20 g of WAY-100634 (2) and
85 lL of TEA in 3.0 ml of methylene chloride were add-
ed and stirred at room temperature for 2 h. At the end of
the reaction, the solution was loaded onto a flash chro-
matography silica gel column and eluted with ethyl
acetate containing 0.1% TEA to give 140 mg of product
(65%). 1H NMR (CDCl3) d 1.16–1.44 (m, 2H), 1.58–1.63
(m, 2H), 1.86–2.06 (m, 4H), 2.27–2.33 (m, 1H),
2.59–2.66 (m, 6H) 2.99 (s, broad, 4H), 3.84 (s, 3H),
3.99 (t, 2H), 4.71 (dm, JHF = 48.8 Hz, 1H), 6.82–7.03
(m, 4H), 7.21–7.34 (m, 2H), 7.76 (td, 1H), 8.51 (dd,
1H). 13C NMR (CDCl3) d 23.6, 30.0 (d, JCF = 21.5 Hz),
Compound 23: mp 131 ꢁC (d). 1H NMR (CDCl3) d
1.4–1.6 (m, 4H), 1.9–2.1 (m, 4H), 2.2–2.4 (m, 16H), 4.6
(m, 1H), 5.22 (s, 2H), 8.1 (d, 2H), 8.4 (d, 2H). 13C
NMR (CDCl3) d 16.4, 16.8, 17.2, 26.5, 31.3, 41.3, 62.6,
82.4, 124.7, 129.2, 129.2, 133.2, 134.0, 136.4, 143.5,
150.9, 175.0. MS (EI) 446, 412, 363, 322, 308, 286,
271, 225, 203, 160, 147, 131, 108, 81.
Compound 24: mp 137 ꢁC (d). 1H NMR (CDCl3) d
1.4–2.0 (m, 8H), 2.2–2.3 (m, 15H), 2.4 (m, 1H) 4.9 (m,
1H), 5.22 (s, 2H), 8.1 (d, 2H), 8.4 (d, 2H). 13C NMR
(CDCl3) d 16.6, 16.9, 17.3, 23.5, 30.2, 41.1, 62.6, 80.6,
124.6, 129.1, 129.2, 133.1, 134.0, 136.3, 143.5, 150.8,
174.9. MS (EI) 488 (M+), 446, 442, 362, 354, 308, 286,
243, 225, 203, 160, 147, 131, 81.
41.2, 45.4, 50.7, 53.5, 55.4, 56.3, 87.8 (d, JCF
=
168.4 Hz), 111.4, 118.3, 121.1, 122.4, 122.5, 123.0,
138.5, 141.6, 149.5, 152.5, 156.2, 176.6. MS (EI) 440
(M+), 425, 311, 278, 249, 218, 205, 190, 162, 149. Anal.
Calcd (C25H33FN4O2F): C, 68.16; H, 7.55; N, 12.72.
Found, C, 67.85; H, 7.80, N, 12.50. Compounds 13
and 14 are prepared using a similar procedure.
3.10. trans-Pentamethylbenzyl 3-(methanesulfonyl)oxy-
cyclohexanecarboxylate (25)
To a solution of 21 (81 mg, 0.27 mmol) in 2 ml methy-
lene chloride were added methanesulfonyl chloride
(22 ll, 0.28 mmol) and diisopropylethylamine (51 ll,
0.29 mmol). The mixture was stirred at room tempera-
ture overnight. At the end of the reaction, the solution
was loaded on to a 3.8 · 20 cm flash chromatography
silica gel column and eluted with 3% ethyl acetate in
methylene chloride. The fractions containing the prod-
uct were combined and the solvent evaporated to give
3.13. trans-3-Fluoro-N-{2-[4-(2-methoxyphenyl)pipera-
zin-1-yl]ethyl}-N-(2-pyridyl)cyclohexanecarboxamide
(13)
1H NMR (CDCl3) d 1.22–2.22 (m, 9H), 2.58–2.81 (m,
6H), 2.99 (s, broad, 4H), 3.84 (s, 3H), 4.00 (t, 2H),
4.89 (dm, JHF = 48.2 Hz, 1H), 6.83–7.04 (m, 4H),
7.22–7.33 (m, 2H), 7.77 (dt, 1H), 8.53 (dd, 1H). 13C
NMR (CDCl3) d 19.6, 28.7, 30.1 (d, JCF = 21.5 Hz),
33.7 (d, JCF = 20.0 Hz), 36.6, 45.4, 50.8, 53.6, 55.5,
56.4, 89.1 (d, JCF = 167.0 Hz), 111.5, 118.4, 121.2,
122.5, 122.7, 123.1, 138.5, 141.7, 149.6, 152.6, 155.9,
175.9. MS (EI) 440 (M+), 425,311, 218, 205, 190, 162,
149. Purity: 95% by HPLC.
1
55 mg (54%) of white solid. Mp 120–121 ꢁC. H NMR
(CDCl3) d 1.4–1.8 (m, 4H), 1.8–2.0 (m, 4H), 2.1–2.4
(m, 15H), 2.8 (m, 1H), 3.0 (s, 3H), 5.0 (m, 1H), 5.25
(s, 2H). 13C NMR (CDCl3) d 16.6, 16.9, 17.3, 20.0,
28.1, 31.0, 33.4, 38.3, 38.7, 62.7, 78.3, 129.2, 133.1,
134.0, 136.3, 175.2. MS (EI) 382 (M+), 338, 308, 286,
256, 205, 175, 160, 145, 131,108, 81.
3.14. cis-3-Fluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-
yl]ethyl}-N-(2- pyridyl)cyclohexanecarboxamide (14)
3.11. cis-Pentamethylbenzyl 3-(methanesulfonyl)oxycyc-
lohexanecarboxylate (26)
1H NMR (CDCl3) d 1.01–1.14 (m, 1H), 1.26–1.56 (m,
2H), 1.76–1.85 (m, 3H), 1.99–2.38 (m, 3H), 2.59–2.66
(m, 6H), 2.99 (s, broad, 4H), 3.84 (s, 3H), 3.98 (t, 2H),
4.24 (dm, JHF = 48.8 Hz, 1H), 6.82–7.02 (m, 4H),
7.22–7.34 (m, 4H), 7.78 (td, 1H), 8.53 (dd, 1H). 13C
NMR (CDCl3) d 23.0 (d, JCF = 12.2 Hz), 28.4, 32.3 (d,
JCF = 18.1 Hz), 35.6 (d, JCF = 20.0 Hz), 40.4 (d,
JCF = 11.22 Hz), 45.7, 50.8, 53.6, 55.5, 56.3, 91.7 (d,
JCF = 173.3 Hz), 111.5, 118.4, 121.2, 122.3, 122.7,
123.1, 138.6, 141.6, 149.7, 152.6, 156.0, 174.6. MS (EI)
440 (M+), 425,311, 218, 205, 190, 162, 149. Purity:
96% by HPLC.
To a solution of 22 (200 mg, 0.66 mmol) in 4 ml methy-
lene chloride were added methanesulfonyl chloride
(54 ll, 0.68 mmol) and diisopropylethylamine (126 ll,
0.71 mmol). The mixture was stirred at room tempera-
ture overnight. At the end of the reaction, the product
was purified by flash chromatography on silica gel as de-
scribed above to give 146 mg white solid (58%). mp
1
120.0–121.5 ꢁC. H NMR (CDCl3) d 1.2–2.0 (m, 6H),
2.1–2.5 (m, 17H), 3.0 (s, 3H), 4.6 (m, 1H), 5.25 (s,
2H). 13C NMR (CDCl3) d 16.5, 16.9,17.3, 23.4, 27.8,