1540
Vol. 54, No. 11
100 °C) d: 7.40—7.25 (5H, m), 5.07 (2H, s), 4.23 (2H, s), 4.10 (2H, q,
Jꢂ7.2 Hz), 4.05 (2H, s), 4.03 (2H, s), 3.29 (3H, s), 1.17 (3H, t, Jꢂ7.2 Hz).
Tetrahydro-8a-(methoxymethyl)-5-oxo-1ꢀ-(phenylmethyl)-spiro[imi-
dazo[1,2-a]pyrazine-2(3H),4ꢀ-piperidine]-7(1H)-carboxylic Acid Phenyl-
methyl Ester (7) Compound 6 (15.4 g) and 5 (19.0 g) were dissolved in
toluene (300 ml) and the mixture was refluxed for 2.5 h with Dean–Stark ap-
paratus. After cooling, the solvent was removed in vacuo. The residue was
purified by silica gel column chromatography (eluant: Hex/AcOEtꢂ4/1–
2/1–1/1) to afford compound 7 (23.9 g, 85% yield) as a colorless amorphous
solid. MALDI-TOF-HR-MS m/z (MꢄH): Calcd for C27H35N4O4S:
479.2658. Found: 479.2653. 1H-NMR (300 MHz, DMSO-d6, 100 °C) d:
7.37—7.17 (10H, m), 5.14 (1H, d, Jꢂ12.7 Hz), 5.08 (1H, d, Jꢂ12.7 Hz),
4.22 (1H, d, Jꢂ13.2 Hz), 4.18 (1H, d, Jꢂ17.8 Hz), 3.99 (1H, d, Jꢂ11.4 Hz),
3.73 (1H, d, Jꢂ17.8 Hz), 3.46 (2H, s), 3.32 (1H, d, Jꢂ9.9 Hz), 3.25 (1H, d,
Jꢂ9.9 Hz), 3.22 (3H, s), 2.94 (1H, s), 2.86 (1H, d, Jꢂ11.4 Hz), 2.80 (1H, d,
Jꢂ13.2 Hz), 2.58—2.45 (2H, m), 2.29—2.17 (2H, m), 1.75—1.59 (2H, m),
1.44—1.38 (2H, m). 13C-NMR (75 MHz, DMSO-d6, 100 °C) d: 162.93,
153.52, 138.09, 136.21, 128.13 (2C), 127.78 (2C), 127.47 (2C), 127.26,
126.93 (2C), 126.18, 75.81, 74.60, 66.17, 61.44, 58.36, 57.21, 52.04, 49.90,
49.67, 48.71, 45.86, 37.02, 35.87. IR (film) cmꢃ1: 2914, 2848, 1707, 1662,
1454, 1412, 1232, 1120, 739, 698.
Tetrahydro-8a-(methoxymethyl)-5-oxo-1ꢀ-(4-pyridinyl)-spiro[imi-
dazo[1,2-a]pyrazine-2(3H),4ꢀ-piperidine]-7(1H)-carboxylic Acid Phenyl-
methyl Ester (8) [Step 1]: To a solution of compound 7 (18.9 g) in 1,2-
dichloroethane (250 ml) was added 1,8-bis(dimethylamino)naphthalene
(10.2 g). Then a-chloroethyl chloroformate (10.7 ml) was dropwised into the
above solution at 0 °C. After stirring the reaction mixture at ambient temper-
ature for 1 h, the reaction mixture was concentrated in vacuo. The resulting
residue was dissolved in MeOH (250 ml) and the mixture was refluxed for
1 h. After cooling, the solvent was removed under reduced pressure. To the
residue was added water (150 ml) and water layer was washed with Et2O.
Then the Et2O layer was extracted with 1 N HCl and water layer was com-
bined the above water layer which was washed with Et2O. Then the water
layer was alkalified with saturated NaHCO3 aqueous solution to more than
pH 10 and the water layer was concentrated in vacuo. Then it was extracted
with CH2Cl2 and organic layer was dried with anhydrous Na2SO4. The sol-
vent was removed under reduced pressure and the residue was purified by
amino-silica gel column chromatography (Fuji Silysia Chemical Ltd., Chro-
matorex NH®, eluant: Hex/CH2Cl2ꢂ1/4–CH2Cl2/MeOHꢂ19/1) to afford de-
protected compound (13.5 g, 88% yield) as pale yellow oil. 1H-NMR
(300 MHz, DMSO-d6, 100 °C) d: 7.39—7.26 (5H, m), 5.14 (1H, d,
Jꢂ12.7 Hz), 5.08 (1H, d, Jꢂ12.7 Hz), 4.22 (1H, d, Jꢂ13.0 Hz), 4.19 (1H, d,
Jꢂ18.0 Hz), 4.01 (1H, d, Jꢂ11.1 Hz), 3.73 (1H, d, Jꢂ18.0 Hz), 3.33 (1H, d,
Jꢂ9.7 Hz), 3.25 (1H, d, Jꢂ9.7 Hz), 3.23 (3H, s), 2.96—2.75 (4H, m),
2.63—2.46 (2H, m), 1.66—1.48 (2H, m), 1.35—1.27 (2H, m).
Jꢂ17.8 Hz), 3.41 (3H, s), 3.40 (1H, d, Jꢂ9.4 Hz), 3.36 (1H, d, Jꢂ12.7 Hz),
2.99 (1H, d, Jꢂ11.7 Hz), 2.57 (1H, d, Jꢂ12.7 Hz), 1.93—1.73 (2H, m),
1.66—1.53 (2H, m).
[Step 2]: To a solution of the deprotected compound (140 mg) in CH2Cl2
(10 ml) which was afforded in Step 1, was added 6-chloronaphthalene-2-sul-
fonyl chloride (121 mg) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h and then saturated NaHCO3 aqueous solution and a
small amount of 1 N NaOH were added to the reaction mixture at 0 °C. The
mixture was extracted with CH2Cl2 and the organic layer was washed with
brine and dried with anhydrous Na2SO4. The solvent was removed under
reduced pressure and the resulting residue was purified by amino-silica gel
column chromatography (Fuji Silysia Chemical Ltd., Chromatorex NH®,
eluant: Hex/CH2Cl2ꢂ1/3–CH2Cl2) to afford compound 9 (148 mg, 63%
yield) as a pale brown amorphous solid. MALDI-TOF-HR-MS m/z
1
(MꢄH): Calcd for C27H3035ClN5O4S: 556.1785. Found: 556.1781. H-NMR
(300 MHz, CDCl3) d: 8.34 (1H, s), 8.22 (2H, d, Jꢂ6.4 Hz), 8.00—7.90 (3H,
m), 7.78 (1H, dd, Jꢂ1.5, 8.8 Hz), 7.61 (1H, dd, Jꢂ1.8, 8.8 Hz), 6.60 (2H, d,
Jꢂ6.4 Hz), 4.35 (1H, d, Jꢂ16.9 Hz), 4.18 (1H, d, Jꢂ11.7 Hz), 4.18 (1H, d,
Jꢂ11.7 Hz), 3.73 (1H, d, Jꢂ9.5 Hz), 3.53—3.11 (4H, m), 3.48 (1H, d,
Jꢂ9.5Hz), 3.44 (3H, s), 3.31 (1H, d, Jꢂ16.9 Hz), 2.97 (1H, d, Jꢂ11.7 Hz),
2.48 (1H, brs), 2.25 (1H, d, Jꢂ11.7 Hz), 1.91—1.69 (2H, m), 1.47—1.30
(2H, m). 13C-NMR (75 MHz, CDCl3) d: 163.28, 154.34, 150.29 (2C),
135.66, 135.47, 132.90, 130.81, 130.45, 129.07, 128.95 (2C), 126.82,
123.51, 108.54 (2C), 77.36, 74.62, 59.54, 58.34, 53.13, 51.46, 47.65, 43.85,
43.39, 36.74, 35.30. IR (KBr) cmꢃ1: 3435, 2939, 1662, 1597, 1454, 1421,
1350, 1167.
Tetrahydro-8a-(methoxymethyl)-1-methyl-5-oxo-1ꢀ-(4-pyridinyl)-
spiro[imidazo[1,2-a]pyrazine-2(3H),4ꢀ-piperidine]-7(1H)-carboxylic
Acid Phenylmethyl Ester (10) To a solution of compound 8 (3.0 g) in
CH2Cl2 (30 ml) was added paraformaldehyde (0.65 g) and NaBH(OAc)3
(4.32 g). The reaction mixture was refluxed for 5 h. Then paraformaldehyde
was added to the reaction mixture and it was refluxed for another 10 h. Then
10% HCl–MeOH (5 ml) was added to the mixture and it was refluxed for
1 h. After cooling, the reaction mixture was alkalinized with saturated
NaHCO3 aqueous solution and was extracted with CH2Cl2. The organic layer
was washed with brine and was dried with anhydrous Na2SO4. The solvent
was removed under reduced pressure to afford compound 10 (2.85 g, 92%
yield) as a colorless amorphous solid. MALDI-TOF-HR-MS m/z (MꢄH):
Calcd for C26H34N5O4: 480.2611. Found: 480.2583. 1H-NMR (300 MHz,
DMSO-d6, 100 °C) d: 8.13 (2H, dd, Jꢂ1.7, 5.1 Hz), 7.42—7.27 (5H, m),
6.74 (2H, dd, Jꢂ1.7, 5.1 Hz), 5.13 (2H, s), 4.37 (1H, d, Jꢂ12.7 Hz), 4.24
(1H, d, Jꢂ11.6 Hz), 4.23 (1H, d, Jꢂ17.8 Hz), 3.97—3.80 (2H, m), 3.79 (1H,
d, Jꢂ17.8 Hz), 3.45 (1H, d, Jꢂ10.3 Hz), 3.33 (1H, d, Jꢂ10.3 Hz), 3.21 (3H,
s), 3.07 (1H, d, Jꢂ11.6 Hz), 2.92—2.75 (2H, m), 2.86 (1H, d, Jꢂ12.7 Hz),
2.34 (3H, s), 1.97—1.85 (1H, m), 1.80—1.57 (2H, m), 1.28—1.17 (1H, m).
13C-NMR (75 MHz, DMSO-d6, 100 °C) d: 162.59, 153.54 (2C), 149.32
(2C), 136.25, 127.78 (2C), 127.26, 126.95 (2C), 107.85 (2C), 76.69, 74.46,
66.21, 59.54, 58.47, 50.06, 47.23, 46.34, 43.74, 43.56, 31.99, 30.98, 26.42.
IR (film) cmꢃ1: 2916, 2850, 1705, 1660, 1593, 1414, 1234, 989, 735.
7-[(6-Chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-
1-methyl-1ꢀ-(4-pyridinyl)-(spiro[imidazo[1,2-a]pyrazine-2(3H),4ꢀ-
piperidin]-5(1H)-one (11) [Step 1]: To a solution of compound 10 (1.0 g)
in MeOH (20 ml) was added 10 % Pd/C (190 mg) and the reaction mixture
was stirred under hydrogen atmosphere at ambient temperature over night.
Then Pd/C was removed by Celite® filtration and the filtrate was concen-
trated in vacuo to obtain a deprotected compound (0.72 g, quant.) as a pale
yellow amorphous solid. 1H-NMR (300 MHz, CDCl3) d: 8.26 (2H, d,
Jꢂ6.1 Hz), 6.66 (2H, d, Jꢂ6.1 Hz), 4.53 (1H, d, Jꢂ11.7 Hz), 3.98—3.82
(2H, m), 3.63—3.55 (1H, m), 3.53 (2H, s), 3.47—3.33 (2H, m), 3.36 (3H,
s), 3.05 (1H, d, Jꢂ11.7 Hz), 3.02—2.76 (2H, m), 2.65 (1H, d, Jꢂ12.8 Hz),
2.34 (3H, s), 2.03—1.92 (1H, m), 1.86—1.73 (1H, m), 1.67—1.57 (1H, m),
1.32—1.22 (1H, m).
[Step 2]: To a solution of the deprotected compound (12.0 g) which was
afforded in Step 1 in EtOH (200 ml) were added 4-chloropyridine hy-
drochloride (7.0 g) and i-Pr2NEt (26.9 ml). The mixture was stirred at 150—
160 °C in a sealed tube for 4 h then it was concentrated in vacuo. The re-
sulting residue was purified by amino-silica gel column chromatography
(Fuji Silysia Chemical Ltd., Chromatorex NH®, eluant: Hex/CH2Cl2ꢂ4/1–
CH2Cl2–CH2Cl2/MeOHꢂ99/1) to afford compound 8 (7.27 g, 51% yield) as
a pale brown amorphous solid. MALDI-TOF-HR-MS m/z (MꢄH): Calcd
1
for C25H32N5O4: 466.2454. Found: 466.2478. H-NMR (300 MHz, DMSO-
d6, 100 °C) d: 8.12 (2H, dd, Jꢂ1.7, 5.0 Hz), 7.42—7.26 (5H, m), 6.73 (2H,
dd, Jꢂ1.7, 5.0 Hz), 5.15 (1H, d, Jꢂ12.7 Hz), 5.09 (1H, d, Jꢂ12.7 Hz), 4.24
(1H, d, Jꢂ13.2 Hz), 4.21 (1H, d, Jꢂ18.0 Hz), 4.05 (1H, d, Jꢂ11.1 Hz), 3.76
(1H, d, Jꢂ18.0 Hz), 3.50—3.22 (6H, m), 3.24 (3H, s), 2.96 (1H, d,
Jꢂ11.1 Hz), 2.85 (1H, d, Jꢂ13.2 Hz), 2.78 (1H, s), 1.85—1.65 (2H, m),
1.56—1.46 (2H, m). 13C-NMR (75 MHz, DMSO-d6, 100 °C) d: 162.97,
153.69, 153.54, 149.33 (2C), 136.20, 127.78 (2C), 127.27, 126.95 (2C),
107.86 (2C), 76.03, 74.69, 66.19, 58.38, 57.33, 52.29, 48.71, 45.89, 42.99,
42.66, 35.91, 34.62. IR (film) cmꢃ1: 2914, 2848, 1705, 1660, 1595, 1412,
1232, 1120, 987, 733.
[Step 2]: To a solution of the deprotected compound (140 mg) in CH2Cl2
(10 ml) which was afforded in Step 1, was added 6-chloronaphthalene-2-sul-
fonyl chloride (117 mg) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h and then saturated NaHCO3 aqueous solution was added
to the reaction mixture at 0 °C. The mixture was extracted with CH2Cl2 and
the organic layer was washed with brine and dried with anhydrous Na2SO4.
The solvent was removed under reduced pressure and the resulting residue
was purified by amino-silica gel column chromatography (Fuji Silysia
Chemical Ltd., Chromatorex NH®, eluant: Hex/CH2Cl2ꢂ1/3–CH2Cl2) to af-
ford compound 11 (166 mg, 72% yield) as a pale brown amorphous solid.
MALDI-TOF-HR-MS m/z (MꢄH): Calcd for C28H3235ClN5O4S: 570.1942.
Found: 570.1948. 1H-NMR (300 MHz, CDCl3) d: 8.38—8.33 (1H, m),
7-[(6-Chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-
1ꢀ-(4-pyridinyl)-spiro[imidazo[1,2-a]pyrazine-2(3H),4ꢀ-piperidin]-
5(1H)-one (9) [Step 1]: To a solution of compound 8 (1.0 g) in MeOH
(20 ml) was added 10% Pd/C (190 mg) and the reaction mixture was stirred
under hydrogen atmosphere at ambient temperature over night. Then Pd/C
was removed by Celite® filtration and the filtrate was concentrated in vacuo
to obtain a deprotected compound (0.7 g, 98% yield) as a pale yellow amor-
1
phous solid. H-NMR (300 MHz, CDCl3) d: 8.25 (2H, dd, Jꢂ1.5, 5.1 Hz),
6.67 (2H, dd, Jꢂ1.5, 5.1 Hz), 4.32 (1H, d, Jꢂ11.7 Hz), 3.67 (1H, d,
Jꢂ9.4 Hz), 3.62 (1H, d, Jꢂ17.8 Hz), 3.55—3.27 (4H, m), 3.48 (1H, d,