J. Andries et al. / European Journal of Medicinal Chemistry 46 (2011) 3455e3461
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1 ml of DMF) and the resulting solution was washed several times
with 10% LiCl and brine. The organic layer was dried over MgSO4
and concentred in vacuo to afford the expected product with
a satisfactory purity, without further purification.
4-fluorobenzenesulfonylchloride, 1.05 eq.) at 0 ꢁC. After stirring at
0 ꢁC for 3 h, the mixture was washed with 10% NaOH and brine. The
organic layer was dried over MgSO4, evaporated and purified by
column chromatography on silica gel (pre-treated with triethyl-
amine and using dichloromethane/MeOH (98:2) as eluant.
4.1.2. Tert-butyl (2R)-2-[2-(4-methylpiperidin-1-yl)-2-oxoethyl]
pyrrolidine-1-carboxylate (11)
4.1.8. 1-(2-{(2R)-1-[(4-Fluorophenyl)sulfonyl]pyrrolidin-2-yl}
ethyl)-4-methylpiperidine (2a, 4FP3)
Yellow oil (Complex mixture of 4 rotamers). 1H NMR:
d
¼ 0.93 (d,
J ¼ 6.1, 3H), 1.06 (m, 2H), 1.45 (s, 9H), 1.63 (m, 3H), 1.85 (m, 4H), 2.26
Beige solid. Mp < 40 ꢁC. 1H NMR:
d
¼ 0.91 (d, J ¼ 6.36, 3H), 1.24
(m, 1H), 2.51 (m, 1H), 2.95 (m, 2H), 3.33 (m, 2H), 4.07 (m, 2H), 4.54
(m, 2H), 1.35 (m, 1H), 1.57 (m, 6H), 1.79 (m, 1H), 1.92 (m, 2H), 2.07
(m, 1H), 2.38 (m, 2H), 2.85 (bd, J ¼ 11.1, 1H), 2.95 (bd, J ¼ 11.1, 1H),
3.15 (m, 1H), 3.39 (m, 1H), 3.66 (m, 1H), 7.18 (t, J ¼ 8.7, 2H), 7.84 (dd,
(m,1H). 13C NMR:
d
¼ 21.3, 21.4, 22.2, 23.1, 28.1, 29.5, 30.3, 30.6, 30.7,
33.4, 34.3, 34.4, 34.6, 37.2, 37.4, 37.9, 41.4, 41.5, 45.5, 45.7, 45.9, 46.2,
54.1(bs), 79.1, 79.6, 153.8, 153.9, 168.5, 168.7. Anal. Calcd for
C17H30N2O3: C, 65.77; H, 9.74; N, 9.02. Found: C, 65.97; H, 9.91; N,
8.84.
J ¼ 5.13, 8.7, 2H). 13C NMR:
¼ 22.0, 24.2, 30.9, 31.0, 33.6, 34.4, 49.0,
d
53.9, 54.5, 55.7, 59.1, 116.3 (d, JCeF ¼ 22.4), 130.2 (d, JCeF ¼ 9.2), 134.1
(d, JCeF ¼ 3.3), 165.2 (d, JC-F ¼ 254.4). 19F NMR:
¼ ꢀ106,1 (m). Anal.
d
Calcd for C18H27FN2O2S: C, 60.99; H, 7.68; N, 7.90. Found: C, 61.13; H,
7.84; N, 8.12.
4.1.3. Tert-butyl (2R)-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]-2-
oxoethyl}pyrrolidine-1-carboxylate (12)
Yellow oil (Complex mixture of 4 rotamers). 1H NMR:
d
¼ 1.40 (s,
4.1.9. 1-(2-{(2R)-1-[(2-Fluorophenyl)sulfonyl]pyrrolidin-2-yl}
ethyl)-4-methylpiperidine (2b, 2FP3)
9H), 1.84 (m, 4H), 2.19 (m, 1H), 3.01 (m, 5H), 3.28 (m, 2H), 3.67 (m,
4H), 3.78 and 3.79 (2s, 3H), 4.03 (m, 1H), 6.90 (m, 4H). 13C NMR:
Yellow oil. 1H NMR:
d
¼ 0.95 (d, J ¼ 5.3, 3H),1.41 (m, 3H),1.79 (m,
7H), 2.11 (m, 3H), 2.60 (m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 3.93 (m,
1H), 7.24 (m, 2H), 7.57 (m, 1H), 7.91 (m, 1H). 13C NMR:
d
¼ 23.0, 23.9, 28.8, 28.9, 30.2, 31.2, 38.1, 38.6, 42.1, 46.4, 46.7, 47.1,
50.9, 51.7, 52.0, 54.9, 55.0, 55.7, 55.8, 111.6, 118.6, 118.7, 121.4, 123.6,
123.7, 141.1, 141.2, 152.6, 152.6, 154.7, 154.8, 169.6, 169.8. Anal. Calcd
for C22H33N3O4: C, 65.48; H, 8.24; N, 10.41. Found: C, 65.59; H, 7.87;
N, 10.59.
d
¼ 22.0, 24.6,
30,7, 31.6, 32.7, 33.6, 48.7 (d, JCeF ¼ 2.6) 54.0, 54.2, 55.6, 59.1 (d,
JCeF ¼ 3.1), 117.6 (d, JCeF ¼ 22.3), 124.8 (d, JCeF ¼ 3,8), 126.75 (d,
JCeF ¼ 15.2), 132.1, 135.2 (d, JCeF ¼ 8.5), 159.2 (d, JCeF ¼ 254). 19F
NMR:
d
¼ ꢀ107,7 (m). Anal. Calcd for C18H27FN2O2S: C, 60.99; H,
4.1.4. General procedure for the reduction with LiAlH4 of 11 and 12
To a solution of LiAlH4 (2.1 eq.) in anhydrous THF (3 ml per
mmol LiAlH4), under inert atmosphere and at 0 ꢁC, was slowly
added a solution of the amide compound (11 or 12, 1 eq.) in
anhydrous THF. The reaction was then allowed to reach room
temperature, stirred for 210 min and then quenched at 0 ꢁC with
aqueous saturated NH4Cl solution. The resulting mixture was
filtered over Celite and extracted with dichloromethane. The
combined organic layers were dried over MgSO4 and evaporated to
afford the expected product.
7.68; N, 7.90. Found: C, 60.67; H, 7.40; N, 8.02.
4.1.10. 4-Methyl-1-(2-{(2R)-1-[(4-nitrophenyl)sulfonyl]pyrrolidin-
2-yl}ethyl)piperidine (4a, 4NP3)
Beige solid. Mp ¼ 132e134 ꢁC. 1H NMR:
¼ 0.95 (d, J ¼ 6.4, 3H),
d
1.36 (m, 3H), 1.61 (m, 6H), 1.90 (m, 3H), 2.13 (m, 1H), 2.39 (m, 2H),
2.87 (d, J ¼ 10.9,1H), 2.99 (d, J ¼ 10.9,1H), 3.21 (m,1H), 3.48 (m,1H),
3.76 (m, 1H), 8.04 (d, J ¼ 9.0, 2H), 8.39 (d, J ¼ 9.0, 2H). 13C NMR:
d
¼ 22.3, 24.5, 31.2, 31.3, 33.8, 34.7, 49.4, 54.1, 54.9, 55.9, 59.7, 124.7,
129.0, 144.1, 150.4. Anal. Calcd for C18H27N3O4S: C, 56.67; H, 7.13.
Found: C, 56.78; H, 6,84.
4.1.5. Tert-butyl (2R)-2-[2-(4-methylpiperidin-1-yl)ethyl]
pyrrolidine-1-carboxylate (13)
4.1.11. 4-Methyl-1-(2-{(2R)-1-[(2-nitrophenyl)sulfonyl]pyrrolidin-
Yellow oil (Mixture of 2 rotamers). 1H NMR:
d
¼ 0.89 (m, 3H),
2-yl}ethyl)piperidine (4b, 2NP3)
1.25 (m, 3H), 1.44 (s, 9H), 1.59 (m, 3H), 1.88 (m, 7H), 2.31 (m, 2H),
2.88 (m, 2H), 3.58 (m, 2H), 3.75 (bs, 1H). (Conform to literature
[18a]).
Yellow oil. 1H NMR:
d
¼ 0.94 (d, J ¼ 6.3, 3H),1.31 (m, 3H),1.64 (m,
3H), 1.77 (m, 2H), 2.00 (m, 5H), 2.39 (m, 2H), 2.90 (m, 2H), 3.46 (m,
2H), 4.00 (m, 1H), 7.60 (m, 1H), 7.70 (m, 2H), 8.04 (m, 1H). 13C NMR:
d
¼ 22.2, 24.6, 31.1, 31.5, 33.1, 34.5, 49.1, 54.3, 54.5, 55.9, 59.8, 124.3,
4.1.6. Tert-butyl (2R)-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]
ethyl}pyrrolidine-1-carboxylate (14)
131.29, 131.8, 132.7, 133.8, 148.9. Anal. Calcd for C18H27N3O4S: C,
56.67; H, 7.13. Found: C, 56.91; H, 6.87.
Yellow oil (Mixture of 2 rotamers). 1H NMR:
d
¼ 1.46 (s, 9H), 1.68
(m, 1H), 1.87 (m, 5H), 2.44 (m, 2H), 2.67 (m, 3H), 3.08 (m, 5H), 3.32
(m, 2H), 3.75 (m, 1H), 3.86 and 3.87 (2s, 3H), 6.93 (m, 4H). Anal.
Calcd for C22H35N3O3: C, 67.83; H, 9.06; N, 10.79. Found: C, 68.10; H,
9.34; N, 11.08.
4.1.12. 1-(2-{(2R)-1-[(4-Fluorophenyl)sulfonyl]pyrrolidin-2-yl}
ethyl)-4-(2-methoxyphenyl) piperazine (3a, 4FPMP)
Yellow oil. 1H NMR:
d
¼ 1.54 (m, 4H), 1.75 (m, 1H), 2.08 (m, 1H),
2.43 (m, 2H), 2.63 (bm, 4H), 3.09 (m, 5H), 3.35 (m, 1H), 3.67 (m, 1H),
3.80 (s, 3H), 6.88 (m, 4H), 7.13 (m, 2H), 7.79 (m, 2H). 13C NMR:
4.1.7. General procedure: synthesis of 2e5
d
¼ 24.5, 31.3, 33.7, 49.4, 51.0, 53.9, 55.6, 55.8, 59.2, 111.6, 118.6,
Deprotection of tert-butyloxycarbonyl (Boc) was done by dis-
solving the compound (13 or 14) in a Trifluoroacetic acid (TFA)/
dichloromethane (1:3) mixture. The solution was stirred overnight
at 50 ꢁC and the volatile part was removed under reduced pressure.
The resulting mixture was dissolved in dichloromethane and
washed several times with sat. Na2CO3. The organic layer was dried
over MgSO4 and evaporated to give the crude product used as such
in the next step. To a mixture of the previous crude (1 eq.) and
triethylamine (3 eq.) in dichloromethane (30 ml per mmol of
starting amine), under inert atmosphere, was added the proper
sulfonylchloride (2- or 4-nitrobenzenesulfonylchloride, 2- or
121.4, 123.4, 141.7, 152.7, 116.7 (d, JCeF ¼ 22.4), 130.5 (d, JCeF ¼ 9.2),
134.3 (d, JCeF ¼ 3.3), 165.49 (d, JCeF ¼ 254.5). 19F NMR:
d
¼ ꢀ106.0
(m). Anal. Calcd for C23H30FN3O3S: C, 61.72; H, 6.76; N, 9.39. Found:
C, 61.91; H, 7.03; N, 9.63.
4.1.13. 1-(2-{(2R)-1-[(2-Fluorophenyl)sulfonyl]pyrrolidin-2-yl}
ethyl)-4-(2-methoxyphenyl)piperazine (3b, 2FPMP)
¼ 1.49e2.41 (m, 6H), 2.67e3.57 (m, 12H),
3.88 (s, 3H), 4.02 (m, 1H), 6.99 (m, 4H), 7.28 (m, 2H), 7.60 (m, 1H),
7.93 (m, 1H). 13C NMR:
¼ 24.5, 31.7, 31.9, 48.8 (d, JCeF ¼ 2.2), 49.0,
53.3, 55.4, 55.8, 58.6 (d, JCeF ¼ 3.9), 111.7, 117.7 (d, JCeF ¼ 22.6),
Yellow oil. 1H NMR:
d
d