Journal of Medicinal Chemistry
Drug Annotation
2
,2,4-Trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]-
2H), 4.54 (s, 2H), 3.81 (s, 3H), 3.63 (br s, 2H), 3.18 (s, 2H), 3.06 (t,
undecan-3-one Hydrochloride (14m) (Representative Exam-
ple of Scheme 3 Bearing Disubstitution in Position 2). To a
solution of 4-((methylamino)methyl)-1-phenethylpiperidin-4-ol (22,
J = 11.4 Hz, 2H), 1.86 (d, J = 13.5 Hz, 2H), 1.43 (s, 9H), 1.48−1.34
(
4
m, 4H), 0.98 (q, J = 4.5 Hz, 2H). HPLC−MS: purity 95%, m/z =
+
17.2 [M + H] .
4
96 mg, 2.00 mmol) in DCM (64 mL), NaHCO (337 mg, 4.01
3
Step 3: To a solution of 24 (1.50 g, 3.60 mmol) in DCM (36 mL),
mmol) was added at rt. Finally, 2-bromoisobutyryl bromide (0.30 mL,
.41 mmol) was added dropwise under a nitrogen atmosphere, and
the reaction mixture was stirred at rt overnight. 0.1 M K CO was
added, the phases were separated, and the aqueous phase was back-
extracted with DCM. The combined organic phases were dried over
trifluoroacetic acid (2.8 mL, 36.34 mmol) was added, and the reaction
mixture was stirred at rt for 4 h. The solvent was evaporated to
dryness to give 12-(4-methoxybenzyl)-4-oxa-8,12-
diazadispiro[2.1.5.3]tridecan-13-one trifluoroacetate (25 TFA salt)
as a viscous yellow oil (2.30 g, 67 wt %, quantitative). The crude
2
2
3
MgSO , filtered, and concentrated to dryness to give crude 2-bromo-
4
product was used in the following step without further purification.
1
N-((4-hydroxy-1-phenethylpiperidin-4-yl)methyl)-N,2-dimethylpro-
panamide as a yellow oil (749 mg, 94%). To a solution of the previous
crude compound (749 mg, 1.88 mmol) in dry THF (32 mL), cooled
to −78 °C under a nitrogen atmosphere, potassium tert-butoxide
solution (3.77 mL, 1 M in THF, 3.77 mmol) was slowly added at −78
H NMR (400 MHz, CDCl ) δ 9.31 (br s, 1H), 8.94 (br s, 1H),
3
7
3
=
.20−7.16 (m, 2H), 6.92−6.84 (m, 2H), 4.54 (s, 2H), 3.80 (s, 3H),
.24 (s, 2H), 3.20 (d, J = 12.1 Hz, 2H), 3.11−2.97 (m, 2H), 2.09 (d, J
14.4 Hz, 2H), 1.75 (td, J = 14.5, 4.3 Hz, 2H), 1.46 (q, J = 4.7 Hz,
2
H), 0.97 (q, J = 4.7 Hz, 2H). HPLC−MS: purity 95%, m/z = 371.1
°
C, and then the reaction mixture was allowed to warm to 0 °C over a
period of 1 h and further stirred at 0 °C for 2 h. Saturated aqueous
NH Cl was then added, and it was extracted with ethyl acetate. The
+
[M + H] .
Step 4: A mixture of 25 TFA salt (1.50 g, 67 wt %, 3.60 mmol), (2-
4
bromoethyl)benzene (0.59 mL, 4.33 mmol), sodium iodide (0.32 g,
2.17 mmol), and K CO (2.49 g, 18.05 mmol) in acetonitrile (36 mL)
combined organic phases were dried over MgSO , filtered, and
concentrated to dryness. The residue was purified by flash
chromatography (SiO , DCM/MeOH up to 10%) to give 2,2,4-
4
2
3
was heated at 80 °C in a sealed tube overnight. Water was added, and
it was extracted with ethyl acetate. The combined organic phases were
2
trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (14m
free base) as an oil (275 mg, 46%). To a solution of the previous
free base (275 mg, 0.87 mmol) in diethyl ether (4 mL), a solution of
HCl (0.52 mL, 2 M in diethyl ether, 1.04 mmol) was added under
stirring, upon which a solid started to precipitate immediately. The
resulting suspension was stirred for 1 h at rt. Then, the solids were
collected by filtration, washed with diethyl ether, and dried under
washed with brine, dried over MgSO , filtered, and concentrated to
dryness. The residue was purified by flash chromatography (SiO2,
DCM/MeOH up to 10%) to give 12-(4-methoxybenzyl)-8-phenethyl-
4
4
-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one (26) as an oil (1.17 g,
1
7
7%). H NMR (400 MHz, CDCl ) δ 7.30−7.25 (m, 2H), 7.23−7.17
3
(
m, 5H), 6.88−6.84 (m, 2H), 4.55 (s, 2H), 3.80 (s, 3H), 3.19 (s, 2H),
2
.80−2.68 (m, 2H), 2.58−2.47 (m, 4H), 2.31 (td, J = 11.4, 2.7 Hz,
H), 1.97−1.87 (m, 2H), 1.66−1.48 (m, 2H), 1.42 (dd, J = 7.9, 4.5
vacuum to obtain 14m HCl salt as a white solid (264 mg, 86% yield).
2
1
H NMR (400 MHz, CD OD) δ 7.39−7.22 (m, 5H), 3.64−3.55 (m,
Hz, 2H), 0.99 (dd, J = 7.9, 4.5 Hz, 2H). HPLC−MS: purity 92%, m/z
3
+
2
3
1
3
H), 3.49 (s, 2H), 3.44−3.36 (m, 2H), 3.34−3.24 (m, 2H), 3.14−
= 421.1 [M + H] .
.06 (m, 2H), 3.03 (s, 3H), 2.10−2.00 (m, 2H), 1.98−1.86 (m, 2H),
Step 5: A mixture of 26 (0.17 g, 0.40 mmol) and CAN (0.57 g, 1.21
mmol) in a mixture of acetonitrile−water 1:1 (4 mL) was stirred at rt
for 7 h. Saturated aqueous Na CO was added, and it was extracted
+
.43 (s, 6H). HPLC−MS: purity 99%. HRMS [M + H] (diff ppm)
17.2234 (−3.4).
2
3
1
2-Methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]-
with ethyl acetate. The combined organic phases were washed with
tridecan-13-one Hydrochloride (14n). Step 1: To a solution of
tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6, 10.00 g, 46.89
mmol) in a mixture of EtOH−water 9:1 (200 mL), 4-methoxybenzyl-
amine (6.43 g, 46.90 mmol) was added. The reaction mixture was
heated at 100 °C overnight in a sealed vessel. The solvent was
removed under vacuum and the residue was purified by flash
brine, dried over MgSO , filtered, and concentrated to dryness. The
4
residue was purified by eluting through an acidic ion-exchange resin
cartridge (SCX) to give 8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]-
tridecan-13-one (27) as a pale brown oil (106 mg, 88%). The crude
product was used in the following step without further purification.
1
H NMR (400 MHz, CDCl ) δ 7.32−7.27 (m, 2H), 7.23−7.17 (m,
3
chromatography (SiO , DCM/MeOH up to 20%) to give tert-butyl 4-
2
3H), 5.83 (br s, 1H, NH), 3.37 (d, J = 2.7 Hz, 2H), 2.84−2.77 (m,
hydroxy-4-(((4-methoxybenzyl)amino)methyl)piperidine-1-carboxy-
2
H), 2.71−2.57 (m, 4H), 2.39 (t, J = 10.2 Hz, 2H), 2.08−2.00 (m,
1
late (23) as a yellow oil (13.55 g, 82%). H NMR (400 MHz, CDCl )
3
2H), 1.79−1.70 (m, 2H), 1.37 (dd, J = 8.0, 4.6 Hz, 2H), 1.02 (q, J =
4
δ 7.25−7.20 (m, 2H), 6.89−6.84 (m, 2H), 3.80 (s, 3H), 3.89−3.70
.6 Hz, 2H).
(
br s, 2H), 3.78 (s, 2H), 3.15 (t, J = 11.7 Hz, 2H), 2.55 (s, 2H),
Step 6: To a solution of 27 (106 mg, 0.35 mmol) in dry THF (3.5
mL), NaH (16 mg, 60 wt % in mineral oil, 0.39 mmol) was added.
The reaction mixture was stirred at rt for 30 min, then iodomethane
1
.54−1.47 (m, 2H), 1.45 (s, 9H), 1.43−1.35 (m, 2H). HPLC−MS:
+
purity 98%, m/z = 351.2 [M + H] .
Step 2: To a solution of compound 23 (9.94 g, 28.36 mmol) and
TEA (9.5 mL, 68.16 mmol) in DCM (500 mL), a solution of 2-
(
0.02 mL, 0.39 mmol) was added, and the resulting mixture was
stirred at rt overnight. Saturated aqueous NaHCO was added, and it
3
19
bromo-4-chlorobutanoyl chloride (9.35 g, 42.53 mmol) in DCM
200 mL) was added dropwise at 0 °C under a nitrogen atmosphere.
The reaction mixture was stirred at 0 °C for 2 h. Saturated aqueous
NaHCO was added, and it was extracted with DCM. The combined
was extracted with DCM. The organic phases were combined, dried
(
over MgSO , filtered, and concentrated to dryness. The residue was
4
purified by flash chromatography (SiO , DCM/MeOH up to 20%) to
2
3
obtain 12-methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]-
tridecan-13-one (14n free base) as a colorless oil (25 mg, 23%). To
a solution of the previous free base (25 mg, 0.08 mmol) in anhydrous
diethyl ether (0.5 mL), HCl (2 M solution in diethyl ether, 0.04 mL,
0.08 mmol) was added. The mixture was stirred at rt for 1 h and then
organic phases were dried over MgSO , filtered, and concentrated to
4
dryness to give crude tert-butyl 4-((2-bromo-4-chloro-N-(4-
methoxybenzyl)butanamido)methyl)-4-hydroxypiperidine-1-carboxy-
late as an orange oil (15.10 g, quantitative). To a solution of the
previous crude compound (14.80 g, 27.72 mmol) in THF (185 mL),
cooled to 0 °C under a nitrogen atmosphere, potassium tert-butoxide
solution (111 mL, 1 M in THF, 111.00 mmol) was slowly added, and
the reaction mixture was stirred at 0 °C for 2 h. Saturated aqueous
it was concentrated to dryness to give 14n HCl salt as a white solid
1
(25 mg, 89%). H NMR (400 MHz, CD OD) δ 7.38−7.24 (m, 5H),
3
3.58 (d, J = 11.6 Hz, 2H), 3.50 (s, 2H), 3.42−3.35 (m, 2H), 3.17 (t, J
= 12.9 Hz, 2H), 3.11−3.05 (m, 2H), 3.01 (s, 3H), 2.30 (d, J = 14.9
Hz, 2H), 1.97 (t, J = 14.3 Hz, 2H), 1.29 (q, J = 4.6 Hz, 2H), 1.14−
NH Cl was then added, and it was extracted with ethyl acetate. The
4
+
organic phases were combined, dried over MgSO , filtered, and
1.05 (m, 2H). HPLC−MS: purity 94%. HRMS [M + H] (diff ppm)
4
concentrated to dryness. The residue was purified by flash
315.208 (−3.92).
chromatography (SiO , DCM/MeOH up to 10%) to give tert-butyl
(R)-4-Ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro-
[5.5]undecan-3-one Hydrochloride (14o). Starting from racemic
4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(14e, 449 mg, prepared following Scheme 1 as described for
2
1
2-(4-methoxybenzyl)-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]-
1
tridecane-8-carboxylate (24) as a yellow oil (5.51 g, 48%). H NMR
400 MHz, CDCl ) δ 7.18 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz,
(
3
M
J. Med. Chem. XXXX, XXX, XXX−XXX