3762 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Grauert et al.
(2m, 1H), 3.81 and 3.82 (2s, 3H), 4.86 (s, 1H), 4.89 (s, 1H),
6.76-7.31 (m, 4H), 7.66 and 8.02 (2s, 1H).
(s, 3H), 1.23 (s, 3H), 1.68 (br s, 1H), 2.03-3.08 (m, 6H), 3.20
(m, 1H), 3.81 (s, 3H), 6.77-7.28 (m, 4H). The mother liquor
was heated for 4 h under reflux to achieve racemization. After
it was cooled, the resulting precipitate was filtered off and was
recrystallized to obtain further 25.
(+)-(2R)-2-(2-Met h oxyp h en yl)m et h yl-3,3-d im et h yl-4-
m eth en ylp ip er id in e Hyd r osu lfa te (26). Compound 26 was
prepared in analogy to 19 and isolated as the sulfuric acid salt;
mp 215-216 °C; [R]D20 ) +73.7° (c 1.0, MeOH). 1H NMR (CD3-
OD): δ 1.25 (s, 3H), 1.36 (s, 3H), 2.33-3.44 (m, 7H), 3.86 (s,
3H), 4.97 (s, 1H), 5.00 (s, 1 H), 6.84-7.38 (m, 4H).
N -F o r m y l-2′-m e t h o x y -5,9-d im e t h y l-6,7-b e n zo m o r -
p h a n (21). A solution of 20 (5.0 g, 19 mmol) in 30 mL of
methane sulfonic acid was heated at 100 °C for 45 min. The
solution was cooled and poured into 100 mL of ice water and
extracted twice with ethyl acetate (50 mL). The combined
organic phases were washed with 20 mL of a 10% aqueous
solution of K2CO3, dried, and filtered, and the solvent was
removed in vacuo to give 4.8 g (96%) of 21 as an oil. The
1
product is a 9:1 mixture of the 9-R and 9-â diastereomere. H
NMR (CDCl3): δ 0.81 (d, 3H, J ) 6.2 Hz), 1.34 and 1.39 (2s,
3H), 1.36-3.39 (m, 7 H), 3.87 (s, 3H), 4.76 and 4.78 (2m, 1H),
6.66-7.26 (m, 3H), 8.02 and 8.28 (2s, 1H).
(-)-(1R)-2′-Met h oxy-5,9-d im et h yl-6,7-b en zom or p h a n
Ta r tr a te (27). A suspension of 26 (5.9 g, 20 mmol) and 9 g of
AlCl3 in 6 mL of dichloromethane was refluxed for 2 h
(temperature of the mixture 46-47 °C). The suspension was
cooled, and 50 mL of dichloromethane and 100 g of ice were
added. After addition of 200 mL of NaOH (10% aqueous
solution), the organic phase was separated, dried, and filtered,
and the solvent was removed in vacuo. The residue was
dissolved in 20 mL of MeOH, and R-(+)-tartaric acid (3.1 g,
20.7 mmol, dissolved in 2 mL of hot water) was added. The
resulting precipitate was diluted with 50 mL of acetone and
filtered off to give 6.7 g (85%) of 27; mp 236-238 °C. 1H NMR
(CD3OD): δ 0.92 (s, 3H), 1.35 (s, 3H), 1.36 (m, 1H), 1.41 (s,
3H), 2.25 (m, 1H), 2.69-3.22 (m, 4H), 3.57 (m, 1H), 3.87 (s,
3H), 4.43 (s, 2H), 6.89 (d, 1H, J ) 8.5 Hz), 7.03 (d, 1H, J ) 8.5
Hz), 7.28 (t, 1H, J ) 8.5 Hz).
(-)-(1R ,9r)-2′-Me t h oxy-5,9-d im e t h yl-6,7-b e n zom or -
p h a n Ta r tr a te (22). A solution of 21 (4.8 g, 18.5 mmol) in 50
mL of propanol and 50 mL of hydrochloric acid (32%) was
refluxed for 8 h. The solvent was removed in vacuo, and 50
mL of water was added to the residue and washed with 50
mL of toluene. Afterward, the water solution was alkalized
with 5 g of K2CO3 and twice extracted with 100 mL of ethyl
acetate. The combined organic phase was dried and filtered,
and the solvent was removed in vacuo. The residue was
dissolved in 40 mL of ethanol, and R-(+)-tartaric acid (2.8 g,
18.7 mmol) was added. The resulting precipitate was filtered
off and recrystallized twice from methanol to give 1.7 g (24%)
of 22; mp 234-236 °C. 1H NMR (CDCl3): of the base δ 0.81
(d, 3H, J ) 6.5 Hz), 1.36 (s, 3H), 1.88 (s, 1H), 1.34-3.05 (m,
7H), 3.15 (m, 1H), 3.83 (s, 3 H), 6.69 (d, 1H, J ) 8.4 Hz), 6.87
(d, 1H, J ) 8.4 Hz), 7.16 (t, 1H, J ) 8.4 Hz).
(-)-(1R)-2′-Hydr oxy-5,9-dim eth yl-6,7-ben zom or ph an Hy-
d r obr om id e (28). Compound 28 was prepared as described
20
1
for 23; mp > 250 °C; [R]D ) -52.4° (c 1.0, MeOH). H NMR
(CDCl3): of the base δ 0.85 (s, 3H), 1.24 (s, 3H), 1.30 (s, 3H),
1.06-3.24 (m, 7 H), 6.56 (d, 1H, J ) 6.9 Hz), 6.75 (d, 1H, J )
6.9 Hz), 6.90 (br, 2H), 6.96 (t, 1H, J ) 6.9 Hz).
(-)-(1R ,9r)-2′-H yd r oxy-5,9-d im e t h yl-6,7-b e n zom or -
p h a n Hyd r obr om id e (23). A solution of 22 (1.5 g, 6.5 mmol)
in 15 mL of hydrobromic acid (48%) was refluxed for 2 h. The
solvent was removed in vacuo, and 15 mL of THF was added
to the residue. The resulting amorphic precipitate was filtered
off to give 1.5 g (77%) of 23 as the hydrobromic salt.
N-Ben zyl-2-(2-m eth oxyp h en yl)m eth yl-4-m eth yl-2-p ip -
er id en e (31). A solution of 2-methoxybenzyl chloride (31.3 g,
0.20 mol) in 100 mL of ether was added to a slurry of Mg (6.0
g, 0.25 mol) in 50 mL of ether and stirred under reflux. After
1 h, the resulting solution was added to a cooled slurry of
N-benzyl-4-methyl-pyridinium bromide (52.8 g, 0.20 mol) and
stirred for 2.5 h at -10 °C. The mixture was quenched with
100 mL of ammonia chloride solution, the organic phase was
separated and dried, and the solvent was removed in vacuo.
The residue was dissolved in 250 mL of methanol and NaBH4
(9.5 g, 0.25 mol), and 20 mL of 2 N NaOH was added and
stirred for 12 h at room temperature. Subsequently, methanol
was removed in vacuo, and the residue was extracted two
times with 100 mL of ethyl acetate. The combined organic
phase was washed with 50 mL of water, and the solvent was
removed in vacuo. The residue was dissolved in 200 mL of 2
N HCl and extracted two times with 50 mL of ethyl acetate,
and the water solution was neutralized with NaOH and two
times extracted with 150 mL of ethyl acetate. The organic
solvent was dried, and after it was filtered, the solvent was
removed in vacuo to give 31 g of 31 as a crude oil.
(-)-(1R,9r,2′′S)-2-(2-Ben zyloxyp r op yl)-1′-h yd r oxy-5,9-
d im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (12a ). A solu-
tion of S-(-)-2-benzyloxypropionyl chloride (1.1 g, 5.5 mmol)
in 10 mL of dichloromethane was added to a solution of 23
(0.75 g, 2.5 mmol) and N-methylmorpholine (3 mL) in 15 mL
of dichloromethane at 0 °C. The solution was stirred for 0.5 h
at 0 °C and for 0.5 h at ambient temperature. Thereafter, 20
mL of 2 N HCl was added, the organic phase was separated
and dried, and the solvent was removed in vacuo. The residue
was dissolved in 25 mL of THF, and LiAlH4 (0.5 g) was added.
After 1 h, water (2 mL) and a saturated solution of ammonium
tartrate (10 mL) were added. The organic phase was separated,
and the aqueous layer was extracted with ethyl acetate (3 ×
60 mL). The organic phases were combined, dried, and filtered,
and the solvent was removed in vacuo. The residue was
dissolved in ether and converted to the hydrochloride salts
using ethereal hydrogen chloride to give 0.6 g of 12a (55%);
mp 226-227 °C; [R]D20 ) -13.3° (c 1.0, MeOH). 1H NMR (CD3-
OD): δ 0.82 (d, 3H, J ) 7.2 Hz), 1.33 (d, 3H, J ) 7.2 Hz), 1.40
(s, 3H), 1.42-4.17 (m, 10H), 4.50 (d, 1H, J ) 14.2 Hz), 4.75 (d,
1H, J ) 14.2 Hz), 6.68 (d, 1 H, J ) 8.4 Hz), 6.80 (d, 1H, J )
8.4 Hz), 7.07 (t, 1H, J ) 8.4 Hz), 7.26-7.50 (m, 5H). Anal.
(C24H31NO2‚HCl) C, H, N.
2-Ben zyl-2′-m eth oxy-5-m eth yl-6,7-ben zom or p h a n Ox-
a la te (32). A solution of 31 (30.8 g, 100 mmol) in 100 mL of
methane sulfonic acid was heated at 100 °C for 2 h. The
solution was cooled and poured into 300 mL of ice water,
alkalized with ammonia, and extracted twice with 250 mL of
ethyl acetate. The combined organic phase was dried and
filtered, and the solvent was removed in vacuo. The residue
was dissolved in 1 L of MeOH, heated with charcoal, and
filtered over silica gel. The solvent was removed in vacuo, and
the residue was dissolved in ether and treated with oxalic acid
(-)-(1R,9r,2′′R)-2-(2-Ben zyloxyp r op yl)-1′-h yd r oxy-5,9-
d im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (12b). Com-
pound 12b was prepared in an analogous manner; mp 216-
20
1
217 °C; [R]D ) -76.1° (c 1.0, MeOH). H NMR (CD3OD): δ
0.81 (d, 3H, J ) 7.4 Hz), 1.33 (d, 3H, J ) 6.2 Hz), 1.40 (s, 3H),
1.43-3.61 (m, 9H), 4.06 (m, 1H), 4.52 (d, 1H, J ) 14.0 Hz),
4.74 (d, 1H, J ) 14.0 Hz), 6.69 (d, 1 H, J ) 8.4 Hz), 6.81 (d,
1H, J ) 8.4 Hz), 7.08 (t, 1H, J ) 8.4 Hz), 7.26-7.50 (m, 5H).
Anal. (C24H31NO2‚HCl) C, H, N.
1
to give 30.1 g (76%) of 32 as the oxalate; mp 149-152 °C. H
NMR (CD3OD): δ 1.46 (s, 3H), 1.55-3.50 (m, 8H), 3.88 (s, 3H),
3.91 (m, 1H), 4.44 (s, 2H), 6.87 (d, 1H, J ) 8.5 Hz), 7.00 (d,
1H, J ) 8.5 Hz), 7.23 (t, 1H, J ) 8.5 Hz), 7.40-7.59 (m, 5H).
2′-H yd r oxy-5-m et h yl-6,7-b en zom or p h a n H yd r ob r o-
m id e (33). A solution of 32 (30 g, 75 mmol) in 600 mL of
MeOH was mixed with Pd/C (10%, 3 g) and hydrogenated at
60 °C and 5 bar for 2.5 h. Subsequently, 3.4 L of MeOH was
added, the mixture was heated, and the catalyst was filtered
off. After it was cooled, the crystalline material was filtered
and the solution was concentrated until further material
crystallized. After it was cooled, these crystals were also
(+)-(2R)-2-(2-Met h oxyp h en yl)m et h yl-3,3-d im et h yl-4-
p ip er id on e Ta r tr a te (25). A solution of 24 (which has been
prepared according to the method described for 18) (450 g, 1.8
mol) in 1.5 L of acetone was treated with a solution of S-(-)-
tartaric acid (273 g, 1.8 mol) in 0.5 L of water. After 30 min,
the resulting precipitate was filtered off and recrystallized
20
from water to give 249.8 g (35%) of 25; mp 151-152 °C; [R]D
1
) +26.3° (c 1.0, water). H NMR (CDCl3): of the base δ 1.20