F. M. Sabbatini et al. / Bioorg. Med. Chem. Lett. 20 (2010) 623–627
625
CF3
chiral intermediate 7 and final removal of the N-BOC protecting
group followed by separation of the diastereoisomers gave the final
compounds 5a and 5b.
The synthesis of compound 6 is reported in Scheme 5. Hydrost-
annylation reaction of the commercially available methyl 2-propy-
noate 36 afforded intermediate 37, which was transformed into the
COOMe
MeOOC
Sn(Bu)3
b
a
CF3
38
H
COOMe
36
37
c
CF3
CF3
CF3
R
N
H
N
R
d
e
HOOC
F3C
HOOC
F3C
N
N
N
N
CF3
a
b
CF3
CF3
O
O
COOH
40
COOMe
CF3
CF3
CF3
R = BOC
26a, 26b
F3C
39
25
F
24
F
f
41 R = Boc
c
CF3
CF3
R
N
H
R
N
N
R
g
N
N
N
N
N
N
N
CF3
d
CF3
N
N
O
O
O
O
CF3
F3C
CF3
F3C
F
6
42
F
F
28a, 28b
27a, 27b
Scheme 5. Reagents and conditions: (a) Bu3SnH, Pd(PPh3)2Cl2, THF, rt, 100, y = 46%;
(b) DMF, 1-bromo-3,5-bis(trifluoromethyl)benzene, CuI, Pd-tetrakis, y = 21%; (c)
(Me)3SOI, NaH 60%, DMF, rt, 1 h, y = 16%; (d) LiOH, MeOH, reflux, 2 h, y = 100%; (e)
(PhO)2P(O)N3, TEA, 7, toluene, rt, 3 h, then 100 °C, 1 h, y = 56%; (f) MeI, t-BuONa,
THF, rt, 1 h, y = 100%; (g) MeOH, HCl 37%, reflux, 150, y = 54%.
e
H
H
N
N
N
N
O
N
N
f
O
CF3
F3C
CF3
vinylester derivative 38 by Stille-type coupling with commercially
available 1-bromo-3,5-bis(trifluoromethyl)benzene. Then the key
cyclopropanation reaction was performed according to Corey’s
conditions.7 Basic hydrolysis of the ester 39, followed by Curtius-
type rearrangement in the presence of the chiral arylpiperazine
derivative,8 gave intermediate 41. Sequential methylation of the
urea nitrogen atom and removal of the N-BOC protecting group
afforded the final compound 6.
The in vitro affinities of the compounds described above are
shown in Table 1. Compound 1 (cyclization A, Fig. 2) exhibited a
significant drop of affinity with respect to Vestipitant, most likely
as a consequence of the inappropriate spatial orientation of the
urea carbonyl group which, as observed from X-ray analysis of
Vestipitant,6 should lie out of the plane of the piperazine ring.
Conversely, cyclization of type B (Fig. 2) enabled us to identify 3b
as a novel compound retaining good in vitro affinity compared to
Vestipitant (pKi = 9.3 and 9.6, respectively), while the correspond-
ing saturated analogue 4b and the five-membered ring derivative
2b were found to be less active (pKi = 8.2 and 7.2, respectively).
Noteworthy, the introduction of an amino group within the satu-
rated six-membered ring was well tolerated (compound 5b,
pKi = 9.1); this result was particularly significant as for the first
time it was shown that the presence of an additional basic hetero-
atom on the right hand side of the template can be tolerated, sug-
gesting the possible presence of an additional pharmacophoric
point.
F3C
3a, 3b
F
F
4a, 4b
Scheme 3. Reagents and conditions: (a) BuLi, DIPEA, allyl bromide, THF, ꢀ78 °C,
y = 69%; (b) 7, TEA, (PhO)2P(O)N3, toluene, 3 h, rt, reflux, 1 h, y = 37%; (c) THF, allyl
iodide, t-BuONa, rt, 3 h, y = 58%; (d) DCM, rt, 3 h, Grubb’s catalyst ((benzyli-
dene)dichlorobis(tricyclohexylphoshine)ruthenium), y = 67% (diast. 1), y = 62%
(diast. 2); (e) (i) TFA/DCM, 300, rt; (ii) H2O, K2CO3; (iii) HCl 1 M, Et2O, 300, rt,
y = 58% (diast. 1), y = 59% (diast. 2); (f) (i) H2, Pd/C 10%, 1 Atm, rt, 3 h; (ii) TFA/DCM,
rt, 1 h; (iii) K2CO3/H2O; (iv) HCl 1 M, Et2O; y = 32% (diast. 1), y = 25% (diast. 2).
H
N
OEt
N
O
Br
O
O
a
b
CF3
CF3
CF3
CF3
CF3
CF3
31
29
30
c
H
O
R
R
R
N
N
N
N
N
N
N
N
H
f
H
d
O
CF3
CF3
CF3
CF3
CF3
F3C
F
Diastereoisomers 3a, 4a and 5a exhibited reduced in vitro affin-
ity with respect to 3b, 4b and 5b (pKi = 7.7, 7.5 and 7.0,
respectively).
32
33 R = H
34 R = BOC
R = BOC 35a, 35b
R = H 5a, 5b
g
e
Modelling studies using compound 1, the 2S,6R,-diastereoiso-
mer of compound 3a/3b (IUPAC name: (2S)-1-{[(6R)-6-[3,5-bis
(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridinyl]carbonyl}-
2-(4-fluoro-2-methylphenyl)piperazine) and the 2S,2S-diastereo-
isomer of the compound 5a/5b (IUPAC name: (2S)-2-[3,5-bis
(trifluoromethyl)phenyl]-1-{[(2S)-2-(4-fluoro-2-methylphenyl)-1-
Scheme 4. Reagents and conditions: (a) (i) Mg, I2, Et2O, reflux, 3 h; (ii) diethyl
oxalate, ꢀ60 °C, rt, y = 63%; (b) NH2CH2CH2NH2, Na2SO4, toluene, reflux, 16 h,
y = 32%; (c) H2, Pd/C, MeOH, 1 atm, rt, 3 h, y = 100%; (d) (i) BH3 THF, reflux, 4 h, (ii)
HCl Et2O, 45 °C, 1 h, y = 67%; (e) (Boc)2O, TEA, 0 °C, 600, y = 100%; (f) triphosgene, 7,
TEA, rt, 1 h, y = 40%; (g) TFA, DCM, H2O, K2CO3, HCl Et2O, y = 48% (diast. 1), y = 30%
(diast. 2).