354
R.L. Hudkins et al. / European Journal of Medicinal Chemistry 95 (2015) 349e356
DMSO-d
6
)
d: 7.29 (m, 2H), 6.94 (m, 3H), 4.24 (m, 2H), 3.92 (m, 2H),
d6)d: 165.5, 159.2, 146.4, 128.7, 127.4, 114.4, 65.1, 63.4, 52.3, 49.2,
3
.17 (s, 3H), 2.32 (m, 1H), 1.06 (d, 3H, J ¼ 6.9 Hz).
25 3 2
30.9, 24.9, 20.9, 18.5, 17.5, 15.3, 7.9; HRMS calcd for C19H N O
[
M þ H]þ 328.2025 found 328.2040.
4.1.4. (R)-2-Methyl-1-((S)-2-methyl-3-phenoxy-propyl)-
pyrrolidine (14)
4
.1.8. (±)5-{4-[(S)-2-Methyl-3-((R)-2-methyl-pyrrolidin-1-yl)-
13 (5.7 g, 23.4 mmol), (R)-2-methylpyrrolidine benzensulfonic
propoxy]-phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (16)
This compound was synthesized using the conditions for 11
using 14 (2.1 g, 8.9 mmol) and 9 (1.0 g, 8.9 mmol) to give 16
acid salt (8.5 g, 35.0 mmol), and potassium carbonate (9.7 g,
7
0.1 mmol), in acetonitrile (100 mL) was stirred at reflux for 24 h.
After cooling to rt, the reaction was filtered and concentrated. The
residue was chromatographed on silica gel (5% MeOH in CH Cl ) to
: 7.27 (m,
H), 6.92 (m, 3H), 3.83 (m, 2H), 3.11 (m, 1H), 2.58 (m, 1H), 2.29 (m,
ꢀ
1
(437 mg, 14%). Mp. 112e115 C. H NMR (400 MHz, DMSO-d6) d:
2
2
10.72 (d, J ¼ 1.8 Hz, 1H), 7.74 (d, J ¼ 7.9 Hz, 2H), 7.00 (d, J ¼ 8.0 Hz,
2
2
1
3
give a colorless oil (4.8 g, 88%). H NMR (400 MHz, CDCl ) d
H), 3.96e3.82 (m, 2H), 3.11e2.98 (m, 1H), 2.67e2.52 (m, 2H),
.36e2.14 (m, 2H) 2.12e1.97 (m, 3H), 1.93e1.83 (m, 1H), 1.83e1.74
2
2
6
H), 2.12 (m, 2H), 1.90 (m, 1H), 1.73 (m, 2H), 1.40 (m, 1H), 1.07 (m,
H); LCMS m/z: 234 (M þ 1).
(m, 1H), 1.72e1.57 (m, 2H), 1.37e1.21 (m, 1H), 1.05e0.96 (m, 6H),
13
0
.73 (q, J ¼ 4.9 Hz, 1H); C NMR (100 MHz, DMSO-d6)
d: 165.5,
159.8, 146.5, 128.3, 127.3, 114.4, 71.6, 59.7, 56.9, 53.9, 32.6, 32.5, 21.5,
4.1.5. (±) 5-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-
[M þ H]þ
27 3 2
19.2, 18.5, 17.5, 15.5, 7.9; HRMS calcd for C20H N O
phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one HCl (11)
3
42.2182 found 342.2181.
To a solution of 8 (11.6 g, 52.9 mmol) and 9 (6.5 g, 58.2 mmol) in
ꢀ
1,2-dichloroethane (400 mL) at 0 C was added aluminum tri-
4
.1.9. 2-[4-(3-Chloro-propoxy)-benzoyl]-cyclopropanecarboxylic
chloride (21.2 g, 159 mmol) in portions. The reaction was stirred at
ꢀ
acid methyl ester (19a)
Step 1. A solution of phenol 7a (8.0 g, 85.0 mmol), 1-bromo-3-
chloropropane (8.8 mL, 89.2 mmol) and potassium carbonate
8
0
C for 42 h, then cooled to rt and stirred while ice water was
added. The solid was collected and the layers were separated. The
combined solid and aqueous layer were dissolved in methanol
(35.2 g, 255 mmol), in acetonitrile (100 mL) was stirred at reflux for
(
500 mL) and added concentrated NH
was filtered and then concentrated. To this residue in ethanol
350 mL) was added hydrazine hydrate (15.4 mL, 317 mmol) at
4
OH (40 mL). The solution
2
2 h. The mixture was cooled to rt, diluted with DCM (100 mL),
filtered and concentrated to give a colorless oil (14.0 g, 97%). This
material was used for next step without further purification.
Step 2. To a solution of 17a (6.9 g, 40.5 mmol) and 9 (4.5 g,
(
heated at reflux for 24 h. The reaction was cooled to rt, concen-
trated and the product purified by silica gel chromatography (10%
4
0.5 mmol) in 1,2-dichloroethane (80 mL) was added aluminum
2 2
MeOH in CH Cl ) to give 11 (8.5 g, 49%). The HCl salt was prepared
ꢀ
trichloride (8.10 g, 60.7 mmol) at 0 C. The reaction was then stirred
at 80 C for 1 h, cooled to rt, and crushed-ice added slowly and
stirred until the reaction turned yellow. The reaction was acidified
to pH 1, diluted with ethyl acetate (300 mL) and subsequently
washed with water and brine, dried (Na SO ), and concentrated to
2 4
give 18a. This material in ethyl acetate (100 mL) and was added
trimethylsilyldiazomethane (2.0 M solution in ether, 21 mL,
4
by adding a 1.25 M HCleMeOH solution to the free base in meth-
anol and the product crystallized from MeOHeCH Cl to give a
2 2
ꢀ
white solid.
1H NMR (400 MHz, DMSO-d6)
d
: 10.74 (d, J ¼ 1.5 Hz, 1H),
1
0.67e10.55 (m, 1H), 7.76 (d, J ¼ 8.0 Hz, 2H), 7.03 (d, J ¼ 9.0 Hz, 2H),
4.18e4.09 (m, 2H), 3.68e3.56 (m, 1H), 3.49e3.36 (m, 2H),
.14e3.00 (m, 2H), 2.67e2.59 (m, 1H), 2.28e2.10 (m, 3H), 2.10e2.01
3
2 mmol) and stirred 16 h. The solution was concentrated and the
(
m, 1H), 2.01e1.87 (m, 2H), 1.83e1.75 (m, 1H), 1.71e1.58 (m, 1H),
13
product was purified by silica gel chromatography (25% EtOAc in
1
.41 (d, J ¼ 6.5 Hz, 3H), 0.74 (q, J ¼ 4.9 Hz, 1H); C NMR (100 MHz,
1
hexanes) to give 19a as colorless oil (9.0 g, 75%). H NMR (CDCl
.01 (m, 2H), 6.94 (m, 2H), 4.19 (m, 2H), 3.75 (m, 2H), 3.56 (s, 3H),
2.76 (m, 1H), 2.27 (m, 3H), 1.89 (m, 1H), 1.35 (m, 1H); LCMS m/z: 265
Mꢂ OMe).
3
, d):
DMSO-d6) d: 165.5, 159.2, 146.4, 128.7, 127.5, 114.4, 65.1, 63.4, 52.3,
8
4
25 3 2
9.2, 30.9, 24.9, 20.9,18.5,17.5,15.3, 7.9; HRMS calcd for C19H N O
þ
[M þ H] 328.2025 found 328.2023.
(
11 was separated by chiral SCF chromatograph (MeOH, 0.1%
DEA, chira-cel OD-H 4.6 ꢁ 250 cm, 2.5 mL/min) to produce isomers
2
5 and 26.
4.1.10. 2-[4-(3-Chloro-propoxy)-benzoyl)-cyclopropanecarboxylic
acid methyl ester (19b)
4
.1.6. (1R,6S)-5-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-
Step 1. 3-Methylphenol 7b (10.6 g, 98.0 mmol), 1-bromo-3-
chloropropane (16.2 g, 103 mmol) and potassium carbonate
(40.6 g, 294 mmol) in acetonitrile (100 mL) was stirred at 85 C for
24 h. After cooling to rt, the reaction was filtered and concentrated
to give 17b (18.0 g, 99%). This material was used for next step
without further purification.
phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (25)
1
ꢀ
H
NMR (400 MHz, DMSO-d6)
0.72e10.62 (m, 1H), 7.79e7.73 (m, 2H), 7.03 (d, J ¼ 8.0 Hz, 2H),
.19e4.08 (m, 2H), 3.66e3.55 (m,1H), 3.52e3.34 (m, 2H), 3.15e2.98
m, 2H), 2.69e2.59 (m, 1H), 2.32e2.09 (m, 3H), 2.09e2.00 (m, 1H),
.00e1.85 (m, 2H), 1.84e1.74 (m, 1H), 1.72e1.57 (m, 1H), 1.41 (d,
d:
10.76e10.72 (m, 1H),
1
4
(
2
Step 2. To a stirred solution of 17b (5.7 g, 26.8 mmol) and 9
(3.0 g, 26.8 mmol) in 1,2-dichloroethane (50 mL) was added
13
J ¼ 6.5 Hz, 3H), 0.74 (q, J ¼ 4.9 Hz, 1H); C NMR (100 MHz, DMSO-
ꢀ
d6) : 165.5, 159.2, 146.4, 128.7, 127.4, 114.4, 65.1, 63.4, 52.3, 49.2,
d
aluminum trichloride (4.65 g, 34.8 mmol) at 0 C. After stirring at
3
[
0.9, 24.9, 20.9, 18.5, 17.5, 15.3, 7.9; HRMS calcd for C19
H
25
N
3
O
2
room temperature for 2 h, crushed-ice water (50 mL) was added
and extracted with ethyl acetate. The organic layer was washed
with brine, dried (Na SO ), and concentrated to give 18b. This
2 4
M þ H]þ 328.2025 found 328.2035.
4
.1.7. (1S,6R)-5-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-
material in methanol (35 mL) was added trimethylsilyldiazo-
methane (2.0 M solution in ether, 37 mL, 74 mmol). The reaction
was stirred for 1 h, concentrated and the product was purified by
phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (26)
1
H NMR (400 MHz, DMSO-d6)
0.71e10.58 (m, 1H), 7.76 (d, J ¼ 9.0 Hz, 2H), 7.03 (d, J ¼ 8.8 Hz, 2H),
.19e4.08 (m, 2H), 3.67e3.55 (m,1H), 3.53e3.35 (m, 2H), 3.15e2.98
m, 2H), 2.68e2.59 (m, 1H), 2.31e2.10 (m, 3H), 2.09e2.01 (m, 1H),
.01e1.86 (m, 2H), 1.84e1.75 (m, 1H), 1.71e1.58 (m, 1H), 1.41 (d,
d: 10.73 (d, J ¼ 1.5 Hz, 1H),
1
4
(
2
silica gel chromatography (25% EtOAc in hexanes) to give 19b as a
1
yellow oil (7.74 g 93%). H NMR (CDCl
3
)
d: 7.89 (s, 1H), 6.77 (m, 2H),
4.16 (m, 2H), 3.74 (m, 2H), 3.58 (s, 3H), 2.69 (m, 1H), 2.54 (s, 3H),
2.31 (m, 1H), 2.25 (m, 2H), 1.90 (m, 1H), 1.33 (m, 1H); LCMS m/z: 279
(M ꢂ OMe).
13
J ¼ 6.3 Hz, 3H), 0.74 (q, J ¼ 5.0 Hz, 1H); C NMR (100 MHz, DMSO-