Antagonists at R1d Adrenergic Receptor
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 8 1913
adsorbed on silica gel and purified by flash chromatography
(cyclohexane/ethyl acetate 7:3) to give 0.09 g (45%) of 8a . H
NMR (CDCl3, δ): 1.59-1.88 (m, 1H, exchanged with D2O), 3.36
(t, 2H, J ) 5.6 Hz), 3.93 (t, 2H, J ) 5.6 Hz), 4.57-4.84 (m,
1H,), 6.63 (dd, 2H, J ) 3,7, and 7.5 Hz), 7.17 (d, 1H, J ) 7.5
Hz).
added and the solution was extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were washed with H2O, dried
(Na2SO4), filtered, and evaporated to dryness at reduced
pressure. The crude was purified by flash chromatography
(cyclohexane/ethyl acetate 9:1) to give 0.08 g (38%) of 17. H
NMR (CDCl3, δ): 3.19 (s, 3H), 3.37 (d, 1H), 3.64 (d, 1H), 7.26
(d, 1H), 7.37 (dd, 1H), 7.45 (d, 1H).
1
1
(b) N-(2,5-Dich lor oph en yl)-2-m eth ylam in oeth an ol (9a).
A mixture of 8a 21 (0.21 g, 1 mmol), 37% HCHO (0.08 mL, 3
mmol), and formic acid (0.14 g, 3 mmol) was refluxed for 18 h.
After the mixture was cooled, 12 N HCl was added until pH
1, the solvent was evaporated to dryness, and the residue was
made alkaline by 2 N NaOH and extracted with CH2Cl2 (3 ×
10 mL). After drying (Na2SO4), the solvent was evaporated
under vacuum and the residue was purified by flash chroma-
tography (petroleum ether/ethyl acetate 8:2) to give 0.05 g
(23%) of 9a . 1H NMR (CDCl3, δ): 2.49-2.63 (m, 1H exchanged
with D2O), 2.77 (s, 3H), 3.17 (t, 2H, J ) 5.8 Hz), 3.74 (t, 2H, J
) 5.8 Hz), 6.96 (dd, 2H, J ) 2.9 and 8.8 Hz), 7.06 (d, 1H, J )
2.9 Hz), 7.27 (d, 1H, J ) 8.8 Hz).
(c) N-(2,5-Dich lor op h en yl)-N-m et h yl-2-ch lor oet h yl-
a m in e (11). To an ice-cooled solution of 9a (0.22 g, 1 mmol)
in CH2Cl2 (10 mL) containing three drops of DMF, thionyl
chloride (0.14 g, 1.2 mmol) was added and the mixture was
stirred at room temperature for 0.5 h and then refluxed for 3
h. The solvent was evaporated, and the crude was suspended
in CH2Cl2 (10 mL) and re-evaporated. The residue was made
alkaline by 2 N NaOH and extracted with CH2Cl2 (3 × 10 mL).
After drying (Na2SO4) and evaporation of the solvent under
vacuum, 11 was obtained (0.19 g, 83%), which was used
without further purification. 1H NMR (CDCl3, δ): 2.85 (s, 3H),
3.40 (t, 2H, J ) 7.3 Hz), 3.68 (t, 2H, J ) 7.3 Hz), 6.97 (dd, 1H,
J ) 3.6 and 9.1 Hz), 7.06 (d, 1H, J ) 3.6 Hz), 7.24 (d, 1H, J )
9.1 Hz).
(d ) N,N′-Dim eth yl-N-(2,5-d ich lor op h en yl)eth ylen ed i-
a m in e (14). A mixture of 11 (0.24 g, 1 mmol) and 2 N
methanolic methylamine (4.32 mL, 8.65 mmol) was heated at
60-80 °C for 20 h in an autoclave. After cooling to room
temperature and evaporation of the solvent under vacuum,
the residue was purified by flash chromatography (dichloro-
methane/2 N methanolic ammonia 96:4) to give 0.067 g (29%)
of 14. 1H NMR (CDCl3, δ): 1.93-2.02 (m, 1H, exch with D2O),
2.46 (s, 3H), 2.77 (m, 5H), 3.17 (t, 2H, J ) 6.4 Hz), 6.97 (dd,
1H, J ) 3.2 and 11.8 Hz), 7.06 (d, 1H, J ) 3.2 Hz), 7.24 (d,
1H, J ) 11.8 Hz).
(e) 8-[2-[N-[N-(2,5-Dich lor op h en yl)m et h yla m in o]et h -
yl]m ethylam inoethyl]-8-azaspir o[4.5]decan e-7,9-dion e (92).
Compound 14 was condensed with 2a by heating at 160 °C
for 0.5 h in the presence of TEA. The crude was purified by
flash chromatography (toluene/methanol 95:5) to give 92. The
compound was then transformed into its hydrochloride salt
to further purify it. The free base was eventually reobtained
(see Scheme 3, path a and Table 3). 1H NMR (CDCl3, δ): 1.43-
1.59 (m, 4H), 1.61-1.79 (m, 4H), 2.36 (s, 3H), 2.44-2.73 (m,
8H), 2.82 (s, 3H), 3.09-3.18 (m, 2H), 3.88 (t, 2H, J ) 7.69 Hz),
6.90 (dd, 1H, J ) 11.53 and 3.84 Hz), 7.01 (d, 1H, J ) 3.84
Hz), 7.24 (d, 1H, J ) 11.53 Hz). Anal. (C21H29Cl2N3O2) C, H,
Cl, N.
(c)
2-Am in o-N-(2,5-d ich lor op h en yl)-N-m et h yla cet -
a m id e (19). A mixture of 17 (0.24 g, 0.81 mmol) and 2 N
methanolic ammonia (10 mL, 20 mmol) was heated at 100 °C
in an autoclave for 18 h. After the mixture was cooled to room
temperature, the solvent was evaporated at reduced pressure
and the crude was purified by flash chromatography (CH2Cl2/2
1
N methanolic NH3 97:3) to give 0.10 g (53%) of 19. H NMR
(CDCl3, δ): 1.47-2.06 (br, 2H), 2.94 (d, 1H), 3.11 (d, 1H), 3.19
(s, 3H), 7.22-7.48 (m, 3H).
(d ) 8-[2-[(N-Meth yl-2,5-d ich lor op h en yla m in oca r bon -
ylm eth yl)a m in o]eth yl]-8-a za sp ir o[4.5]d eca n e-7,9-d ion e
(97). A solution of 2a (0.28 g, 1.03 mmol), 19 (0.24 g, 1.03
mmol), and TEA (0.31 g, 3.1 mmol) in toluene (10 mL) was
refluxed for 18 h. After cooling to room temperature, the
solvent was evaporated in vacuo and the residue was purified
by flash chromatography to give 0.04 g of 97 after three
purification steps (toluene/MeOH 96:4, toluene/acetone 8:2,
CH2Cl2/acetone 8:2) (see Scheme 3, path b and Table 3). 1H
NMR (CDCl3, δ): 1.38-1.56 (m, 4H), 1.55-1.77 (m, 4H), 2.36-
2.42 (m, 2H), 2.49 (s, 2H), 3.20 (s, 3H), 3.66-3.78 (m, 2H),
3.79-3.91 (m, 2H), 4.09-4.21 (m, 2H), 7.31-7.39 (m, 2H),
7.43-7.54 (m, 1H). The NH signal was not detectable.
Syn th esis of P h en oxya lk yla m in o Com p ou n d s (98-
104). The synthesis of compound 100 is reported as represen-
tative.
(a ) 1-Br om o-2-(2,5-d ich lor op h en oxy)eth a n e (22). Com-
pound 22 was prepared as indicated in the literature.31
Accordingly, to a mixture of 2,5-dichlorophenol (3 g, 18.4 mmol)
and 1,2-dibromoethane (6.91 g, 36.8 mmol) heated at 100 °C
a solution of NaOH (0.73 g, 18.4 mmol) in H2O (10 mL) was
added dropwise, and the resulting mixture was stirred at 100
°C for 7 h. After 12 h of resting, CH2Cl2 (20 mL) was added,
the organic layer was washed with 2 N NaOH (3 × 15 mL)
and brine (1 × 15 mL), dried over Na2SO4, filtered and
evaporated at reduced pressure. The crude was purified by
flash chromatography (petroleum ether/ethyl acetate 95:5) to
1
give 2.61 g (52%) of 22 as oil. H NMR (CDCl3 δ): 3.67 (t, 2H,
J ) 6.67 Hz), 4.32 (t, 2H, J ) 6.67 Hz), 6.91 (dd, 2H, J ) 10
and 3.34 Hz), 7.29 (d, 1H, J ) 3.34 Hz).
(b) N-Meth yl-2-(2,5-d ich lor op h en oxy)eth yla m in e (27).
A solution of 22 (0.56 g, 2.07 mmol) and 2 N CH3NH2 in MeOH
(9 mL, 18 mmol) was heated at 100 °C in autoclave for 12 h.
After cooling to room temperature, the crude obtained by
evaporation was purified by flash chromatography (CH2Cl2/2
N methanolic ammonia gradient from 98:2 to 95:5) to afford
0.4 g (75%) of 27. 1H NMR (CDCl3 δ): 1.94-2.05 (bs, 1H,
exchanged with D2O), 2.53 (s, 3H), 3.03 (t, 2H, J ) 5.1 Hz),
4.12 (t, 2H, J ) 5.1 Hz), 6.88 (dd, 2H, J ) 10.1 and 3.4 Hz),
7.29 (d, 1H, J ) 3.4 Hz).
(c) 8-[2-[N-2-(2,5-Dich lor op h en oxy)et h yl]-N-m et h yl-
a m in o]eth yl]-8-a za sp ir o[4.5]d eca n e-7,9-d ion e (100). A so-
lution of 2a (0.141 g, 0.51 mmol) and 27 (0.34 g, 1.54 mmol)
in toluene was refluxed for 40 h. After cooling to room
temperature, the solvent was removed at reduced pressure and
the crude was purified by flash chromatography (toluene/
MeOH 95:5), affording 0.06 g of 100. 1H NMR (CDCl3 δ): 1.42-
1.57 (m, 4H), 1.62-1.77 (m, 4H), 2.46 (s, 3H), 2.58 (s, 4H), 2.59
(t, 2H, J ) 6.77 Hz), 2.95 (t, 2H, J ) 5.76 Hz), 3.96 (t, 2H, J
) 6.77 Hz), 4.03 (t, 2H, J ) 5.76 Hz), 6.81-6.97 (m, 2H), 7.20-
7.29 (m, 1H). Anal. (C20H26Cl2N2O3) C, H, Cl, N.
Syn th esis of Am id o Com p ou n d s (95-97). The synthesis
of compound 97 is reported as representative.
(a ) 2-Br om o-N-(2,5-d ich lor op h en yl)a ceta m id e (16). To
a solution of 2,5-dichloroaniline (2 g, 12.3 mmol) in CH2Cl2
(20 mL), cooled at 0 °C, bromoacetyl bromide (1.29 mL, 14.8
mmol) was added, and the resulting mixture was heated at
40 °C for 5 h and then left at room temperature overnight.
The precipitate was filtered off and triturated with petroleum
ether/Et2O (1:3) to give by filtration 1.88 g (54%) of 16. 1H NMR
(CDCl3, δ): 4.07 (s, 2H), 7.08 (dd, 1H), 7.31 (d, 1H), 8.43 (d,
1H), 8.72-8.91 (br, 1H).
Syn t h esis of 8-[2-[4-(Su b st it u t ed p h en yl)-1-p ip er i-
d in yl]eth yl]-8-a za sp ir o[4.5]d eca n e-7,9-d ion es (106-108).
The synthesis of compound 106 is reported as representative.
(a ) Dieth yl 2,5-Dich lor oben zylid en em a lon a te (34c). A
mixture of 2,5-dichlorobenzaldehyde (0.17 g, 1 mmol), diethyl
malonate (0.32 g, 2 mmol), and AlCl3 (0.66 g, 5 mmol) was
stirred at room temperature for 4 h, then poured into ice-
(b )
2-Br om o-N-(2,5-d ich lor op h en yl)-N-m et h yla cet -
a m id e (17). To a suspension of 16 (0.2 g, 0.71 mmol) and
K2CO3 (0.12 g, 0.85 mmol) in DMF (2.5 mL) a solution of CH3I
(0.5 g, 3.53 mmol) in DMF (2.5 mL) was added, and the
resulting mixture was heated at 40 °C for 4 h. After the
mixture was cooled to room temperature, H2O (50 mL) was