4426 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
Malmberg et al.
(R)-2-(Ben zyla m in o)-5-flu or ot et r a lin H yd r och lor id e
(8‚HCl). A mixture of 7 (3.17 g, 7.86 mmol), Et3N (3.28 mL,
23.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf) (435
mg, 0.79 mmol), Pd(OAc)2 (88 mg, 0.39 mmol), and concen-
trated formic acid (0.60 mL, 15.7 mmol) in DMF (50 mL) was
stirred under N2 at 60 °C for 2 h. The mixture was partitioned
between brine, saturated Na2CO3, and ether. The organic
phase was dried (K2CO3), filtered, and concentrated. The
residue was chromatographed [SiO2, MeOH/CH2Cl2 (1:79)
saturated with NH3]. The amine was converted into the
hydrochloride salt, which was recrystallized to afford 2.00 g
of pure 8‚HCl: 1H NMR (CD3OD) δ 1.80-1.96 (m, 1 H), 2.43-
2.50 (m, 1 H), 2.71-2.84 (m, 1 H), 2.93-3.12 (m, 2 H), 3.35-
3.43 (m, 1 H), 3.54-3.65 (m, 1 H), 4.36 (s, 2 H), 6.88-6.95 (m,
1 H), 6.98-7.01 (m, 1 H), 7.14-7.22 (m, 1 H), 7.46-7.59 (m, 5
propanal (0.50 mL, 6.89 mmol), MeOH (5 mL), and NaCNBH3
(433 mg, 6.89 mmol) using method I. After reflux (40 °C) for
7 days propanal (0.40 mL, 5.74 mmol), NaCNBH3 (360 mg,
5.73 mmol), and MeOH (2 mL) were added. After a total of
15 days the reaction was interrupted. The crude oil was
purified by column chromatography [SiO2, MeOH/CH2Cl2 (1:
39) saturated with NH3] followed by preparative TLC (Al2O3,
petroleum ether) to give 29 mg of 15: 1H NMR (CDCl3) δ 0.86
(t, 3 H, J ) 7.4 Hz), 1.05 (d, 6 H, J ) 6.5 Hz), 1.37-1.50 (m,
2 H), 1.53-1.69 (m, 1 H), 1.98-2.08 (m, 1 H), 2.38-2.56 (m, 2
H), 2.56-2.69 (m, 1 H), 2.77-2.81 (m, 2 H), 2.93-3.19 (m, 3
H), 6.76-6.86 (m, 2 H), 7.01-7.09 (m, 1 H); 13C NMR (CDCl3)
δ 11.7, 20.4, 20.9, 22.8 (d, 3J C,F ) 3.7 Hz), 24.4, 27.2, 34.5, 47.6,
2
2
48.6, 54.0, 111.7 (d, J C,F ) 22.0 Hz), 123.9 (d, J C,F ) 17.1
4
3
Hz), 124.7 (d, J C,F ) 3.7 Hz), 126.4 (d, J C,F ) 8.5 Hz), 140.0
3
3
1
H); 13C NMR (CD3OD) δ 21.7 (d, J C,F ) 4.9 Hz), 26.2, 32.8,
(d, J C,F ) 4.9 Hz), 160.9 (d, J C,F ) 242.9 Hz).
2
2
50.0, 55.5, 113.9 (d, J C,F ) 21.9), 123.6 (d, J C,F ) 18.3 Hz),
(R)-2-(Bu tylp r op yla m in o)-5-flu or otetr a lin (16). Com-
pound 16 was prepared from 14 (89 mg, 0.40 mmol), propanal
(0.35 mL, 4.83 mmol), MeOH (5 mL), and NaCNBH3 (303 mg,
4.83 mmol) using method I. After 7 days additional propanal
(0.14 mL, 2.01 mmol) and NaCNBH3 (126 mg, 2.01 mmol) were
added, and after 2 more days the reaction was interrupted.
The residue was chromatographed [SiO2, MeOH/CH2Cl2 (1:
49) saturated with NH3 followed by Al2O3, ether/petroleum
ether (1:19)] to give 65 mg of 16: 1H NMR (CDCl3) δ 0.89 (t,
3 H, J ) 7.4 Hz), 0.91 (t, 3 H, J ) 7.3 Hz), 1.27-1.64 (m, 7 H),
2.01-2.10 (m, 1 H), 2.44-2.53 (m, 4 H), 2.55-3.06 (m, 5 H),
6.77-6.83 (m, 1 H), 6.85-6.88 (m, 1 H), 6.98-7.09 (m, 1 H);
3
3
125.9 (d, J C,F ) 3.6 Hz), 128.8 (d, J C,F ) 8.5 Hz), 130.4 (2C:
3
s), 130.7, 131.1 (2C:s), 132.8, 136.1 (d, J C,F ) 3.7 Hz), 162.1
1
(d, J C,F ) 244.1 Hz).
(R)-2-(Ben zylp r op yla m in o)-5-flu or ot et r a lin H yd r o-
ch lor id e (10‚HCl). Compound 10 was prepared from 8 (653
mg, 2.56 mmol), propanal (1.84 mL, 25.6 mmol), and NaC-
NBH3 (1.61 g, 25.6 mmol) using method I. The reaction time
was 44 h. The residue was purified by chromatography [SiO2,
ether/petroleum ether (1:9) saturated with NH3]. The amine
was converted into the hydrochloride salt to give 662 mg of
10‚HCl. An analytical sample of 10‚HCl was prepared by re-
crystallization: 1H NMR (CD3OD) δ 0.94 (t, 3 H, J ) 7.3 Hz),
1.50-1.92 (m, 2 H), 1.96-2.12 (m, 1 H), 2.40-2.53 (m, 1 H),
2.68-2.81 (m, 1 H), 3.13-3.31 (m, 5 H), 3.70-3.80 (m, 1 H),
4.42-4.59 (m, 2 H), 6.88-6.95 (m, 1 H), 7.01-7.03 (m, 1 H),
7.14-7.22 (m, 1 H), 7.49-7.61 (m, 5 H); 13C NMR (CD3OD) δ
3
13C NMR (CDCl3) δ 11.9, 14.1, 20.7, 22.2, 22.8 (d, J C,F ) 3.6
4
Hz), 25.0, 31.3, 32.0 (d, J C,F ) 2.4 Hz), 50.3, 52.5, 56.2, 111.8
2
2
4
(d, J C,F ) 21.9 Hz), 124.0 (d, J C,F ) 17.1 Hz), 124.7 (d, J C,F
3
3
) 2.4 Hz), 126.4 (d, J C,F ) 8.5 Hz), 139.6 (d, J C,F ) 3.6 Hz),
160.8 (d, J C,F ) 242.9 Hz).
1
3
11.3, 19.5, 22.6 (d, J C,F ) 4.9 Hz), 24.2, 30.3, 53.0, 56.0, 61.0,
(R)-5-F lu or o-2-(p r op yla m in o)t et r a lin H yd r och lor id e
(12‚HCl). Meth od II. A mixture of 10‚HCl (586 mg, 1.76
mmol), Pd(C) (10%, 0.5 g), and MeOH (30 mL) was hydroge-
nated at atmospheric pressure for 25 h. The mixture was
diluted with CH2Cl2/MeOH (4:1) and filtered through Celite.
The volatiles were evaporated under reduced pressure, and
the crude product was recrystallized to give 372 mg of 12‚
HCl: 1H NMR (CD3OD) δ 1.07 (t, 3 H, J ) 7.4 Hz), 1.71-1.91
(m, 3 H), 2.33-2.44 (m, 1 H), 2.71-2.84 (m, 1 H), 2.87-2.97
(m, 1 H), 3.00-3.14 (m, 3 H), 3.27-3.36 (m, 1 H), 3.47-3.58
(m, 1 H), 6.88-6.94 (m, 1 H), 6.97-7.00 (m, 1 H), 7.13-7.21
2
2
113.8 (d, J C,F ) 22.0 Hz), 123.5 (d, J C,F ) 18.3 Hz), 126.1 (d,
4J C,F ) 2.5 Hz), 128.8 (d, J C,F ) 8.5 Hz), 130.5 (2C:s), 131.2,
3
3
1
131.4, 132.2 (2C:s), 136.6 (d, J C,F ) 4.9 Hz), 162.0 (d, J C,F
)
244.1 Hz).
(R)-2-(Ben zylbu tyla m in o)-5-flu or otetr a lin Hyd r och lo-
r id e (11‚HCl). Compound 11 was prepared from 8 (276 mg,
1.08 mmol), butanal (0.97 mL, 10.8 mmol), and NaCNBH3 (679
mg, 10.8 mmol) using method I. Additional butanal (0.292 mL,
3.24 mmol) was added after 5 days, and the reaction mixture
was heated at 40 °C. After a total of 6 days the reaction was
interrupted. The residue was chromatographed [SiO2, ether/
petroleum ether (1:9) saturated with NH3]. The amine was
converted into the hydrochloride salt to give 308 mg of 11‚HCl.
An analytical sample of 11‚HCl (40 mg) was prepared by re-
crystallization: 1H NMR (CD3OD) δ 0.92 (t, 3 H, J ) 7.3 Hz),
1.27-1.40 (m, 2 H), 1.50-1.80 (m, 2 H), 1.96-2.12 (m, 1 H),
2.42-2.52 (m, 1 H), 2.68-2.81 (m, 1 H), 3.11-3.32 (m, 5 H),
3.70-3.82 (m, 1 H), 4.35-4.63 (m, 2 H), 6.88-6.95 (m, 1 H),
7.01-7.03 (m, 1 H), 7.14-7.22 (m, 1 H), 7.49-7.55 (m, 3 H),
7.59-7.64 (m, 2 H); 13C NMR (CD3OD) δ 13.8, 21.0, 22.6 (d,
3J C,F ) 3.6 Hz), 24.3, 28.0, 30.4, 51.3, 56.0, 61.1, 113.8 (d, 2J C,F
3
(m, 1 H); 13C NMR (CD3OD) δ 11.4, 21.0, 21.6 (d, J C,F ) 3.7
4
2
Hz), 26.2, 32.7 (d, J C,F ) 2.4 Hz), 47.9, 55.4, 113.8 (d, J C,F
)
2
4
22.0 Hz), 123.6 (d, J C,F ) 18.3 Hz), 125.9 (d, J C,F ) 3.6 Hz),
128.7 (d, J C,F ) 8.6 Hz), 136.1 (d, J C,F ) 4.9 Hz), 162.0 (d,
3
3
1J C,F ) 242.9 Hz).
(R)-2-Am in o-5-flu or ot et r a lin H yd r och lor id e (9‚H Cl).
Compound 9‚HCl was prepared from 8‚HCl (800 mg, 2.74
mmol), Pd(C) (10%, 0.5 g), and MeOH (250 mL) using method
II. After 20 h the reaction was interrupted. The crude product
was recrystallized to give 511 mg of 9‚HCl: 1H NMR (CD3-
OD) δ 1.78-1.93 (m, 1 H), 2.26-2.32 (m, 1 H), 2.72-3.06 (m,
2
4
) 20.7 Hz), 123.6 (d, J C,F ) 18.3 Hz), 126.1 (d, J C,F ) 2.5
3 H), 3.19-3.26 (m, 1 H), 3.50-3.61 (m, 1 H), 6.87-6.97 (m, 2
Hz), 128.7 (d, 3J C,F ) 8.5 Hz), 130.5 (2C:s), 131.1, 131.7, 132.2
3
H), 7.12-7.20 (m, 1 H); 13C NMR (CD3OD) δ 21.3 (d, J C,F
)
3
1
2
(2C:s), 136.7 (d, J C,F ) 4.9 Hz), 162.0 (d, J C,F ) 244.1 Hz).
(R)-5-F lu or o-2-(2-p r op yla m in o)tetr a lin Hyd r och lor id e
(13‚HCl). Compound 13 was prepared from 9 (214 mg, 1.29
mmol), acetone (0.67 mL, 9.07 mmol), MeOH (5 mL), and
NaCNBH3 (570 mg, 9.07 mmol) using method I. The reaction
time was 24 h. The crude oil was chromatographed [SiO2,
MeOH/CH2Cl2 (1:9) saturated with NH3] to yield 222 mg of
13. A small sample of 13 was converted into the hydrochloride
salt and recrystallized to give 13‚HCl: 1H NMR (CD3OD) δ
1.39 (d, 3 H, J ) 6.4 Hz), 1.40 (d, 3 H, J ) 6.5 Hz), 1.75-1.90
(m, 1 H), 2.32-2.40 (m, 1 H), 2.73-2.95 (m, 2 H), 3.01-3.13
(m, 1 H), 3.25-3.33 (m, 1 H), 3.58-3.71 (m, 2 H), 6.88-6.95
(m, 1 H), 6.97-7.00 (m, 1 H), 7.13-7.21 (m, 1 H); 13C NMR
3.7 Hz), 27.4, 34.1, 48.4, 113.8 (d, J C,F ) 20.8 Hz), 123.5 (d,
2J C,F ) 18.3 Hz), 125.9 (d, J C,F ) 2.4 Hz), 128.6 (d, J C,F ) 8.6
4
3
3
1
Hz), 136.2 (d, J C,F ) 3.7 Hz), 162.1 (d, J C,F ) 244.1 Hz).
(R)-2-(Bu tylam in o)-5-flu or otetr alin Hydr och lor ide (14‚
HCl). Compound 14‚HCl was prepared from 11‚HCl (278 mg,
0.80 mmol), Pd(C) (10%, 0.5 g), and MeOH (15 mL) using
method II. After 24 h the reaction was interrupted. The crude
product was recrystallized to give 188 mg of 14‚HCl: 1H NMR
(CD3OD) δ 1.02 (t, 3 H, J ) 7.3 Hz), 1.48 (sext, 2 H, J ) 7.4
Hz), 1.67-1.91 (m, 3 H), 2.34-2.44 (m, 1 H), 2.71-2.84 (m, 1
H), 2.87-2.97 (m, 1 H), 3.00-3.17 (m, 3 H), 3.28-3.36 (m, 1
H), 3.47-3.58 (m, 1 H), 6.88-6.94 (m, 1 H), 6.97-7.00 (m, 1
H), 7.13-7.21 (m, 1 H); 13C NMR (CD3OD) δ 14.0, 20.9, 21.6
3
3
4
(CD3OD) δ 19.3, 19.7, 21.7 (d, J C,F ) 4.9 Hz), 26.4, 32.8 (d,
(d, J C,F ) 4.9 Hz), 26.2, 29.5, 32.7 (d, J C,F ) 2.4 Hz), 46.1,
2
4J C,F ) 2.4 Hz), 48.6, 52.1, 113.8 (d, J C,F ) 21.9 Hz), 123.7 (d,
55.4, 113.8 (d, 2J C,F ) 21.9 Hz), 123.6 (d, 2J C,F ) 18.3 Hz), 125.9
4
3
4
3
3
2J C,F ) 18.3 Hz), 125.9 (d, J C,F ) 3.7 Hz), 128.7 (d, J C,F ) 8.5
(d, J C,F ) 2.4 Hz), 128.7 (d, J C,F ) 9.7 Hz), 136.1 (d, J C,F
)
3
1
1
Hz), 136.2 (d, J C,F ) 4.9 Hz), 162.0 (d, J C,F ) 244.2 Hz).
(R)-5-F lu or o-2-[(2-p r op yl)p r op yla m in o]t et r a lin (15).
Compound 15 was prepared from 13 (119 mg, 0.574 mmol),
4.9 Hz), 162.0 (d, J C,F ) 242.9 Hz).
(R)-2-[[4-(8-Aza-7,9-dioxospir o[4.5]decan -8-yl)bu tyl]am i-
n o]-5-flu or otetr a lin Hyd r och lor id e (17‚HCl). A mixture