T. Yoshida et al. / Bioorg. Med. Chem. 20 (2012) 5705–5719
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4.1.33. 3-((2S,4S)-4-{4-[1-(5-Cyanopyridin-2-yl)-3-methyl-1H-
pyrazol-5-yl]piperazin-1-yl}pyrrolizin-2-ylcarbonyl)
thiazolidine trihydrochloride (8q)
The title compound was prepared in 72% yield using 12n in the
procedures outlined for 8c. Mp: 210 °C; 1H NMR (300 MHz, DMSO-
d6): d 2.21 (3H, s), 2.25–2.45 (1H, m), 2.95–4.19 (17H, m), 4.47–
4.77 (3H, m), 6.05 (1H, s), 7.97 (1H, d, J = 8.7 Hz), 8.37 (1H, dd,
J = 2.3, 8.7 Hz), 8.93 (1H, d, J = 2.3 Hz), 9.15 (1H, br s), 10.80 (1H,
1.40, 1.44 (9H, s), 1.94–2.10 (2H, m), 2.27 (3H, s). 2.18–2.57 (4H,
m), 2.82–4.12 (11H, m), 4.41–4.76 (3H, m), 5.67 (1H, s), 7.24 (1H,
t, J = 7.3 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.75 (2H, d, J = 7.7 Hz).
To a solution of the above compound (2.67 g, 5.07 mmol) in
dichloromethane (15 mL) was added trifluoroacetic acid (30 mL)
under ice-cooling. The mixture was stirred for 1 h, and then con-
centrated under reduced pressure. The residue was poured into a
saturated aqueous sodium hydrogen carbonate solution and ex-
tracted with chloroform. The extract was washed with brine, dried
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography with chloroform/metha-
nol (10:1, v/v) to give free base of the title compound (1.58 g, 73%)
as an amorphous.
br s); Anal. Calcd for
C
22H28N8OSꢁ3HClꢁ0.2C2H4O2ꢁ1.5H2O: C,
44.77; H, 5.84; N, 18.64. Found: C, 44.54; H, 6.12; N, 18.50; LC–
MS (ESI) m/z 430.4 [M+H]+.
4.1.34. 3-[(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolid
inylcarbonyl]thiazolidine (24)
To a solution of the above compound (1.57 g, 3.68 mmol) in eth-
anol (20 mL) was added a solution of maleic acid (0.854 g,
7.36 mmol) in ethanol (20 mL) under ice-cooling. The precipitate
was collected by filtration to give the title compound (1.77 g, 72%)
as a white powder. Mp: 136 °C; 1H NMR (300 MHz, DMSO-d6): d
2.04–2.15 (1H, m), 2.15 (3H, s), 2.27 (1H, m), 2.43–2.60 (4H, m),
2.73–2.84 (4H, m), 2.95–3.13 (4H, m), 3.42–3.88 (3H, m), 4.40–
4.72 (3H, m), 5.81 (1H, s), 6.15 (4H, s), 7.28 (1H, t, J = 7.5 Hz), 7.45
(2H, t, J = 7.5 Hz), 7.73 (d, J = 7.5 Hz, 2H); Anal. Calcd for
To a solution of N-(tert-Butoxycarbonyl)-cis-4-hydroxy-L-pro-
line (23) (5.00 g, 21.6 mmol) and imidazole (6.48 g, 95.2 mmol)
in DMF (60 mL) was added tert-butyldimethylsilyl chloride
(7.16 g, 47.5 mmol) at room temperature. After stirring at room
temperature for 19 h, to the mixture were added water (60 mL)
and a 10% citric acid aqueous solution (200 mL) under ice-cooling.
The mixture was extracted with ethyl acetate. The extract was
washed with brine, dried and concentrated under reduced pressure
to give (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyl-
oxy)pyrrolidine -2-carboxylic acid (10.9 g) as a light tan solid.
To a solution of the above compound (10.9 g), thiazolidine
(1.9 mL, 24 mmol) and HOBt (3.67 g, 24.6 mmol) in DMF (70 mL)
was added EDC hydrochloride (4.97 g, 25.9 mmol) under ice-cool-
ing. The reaction mixture was stirred at room temperature for 6 h.
The mixture was poured into a saturated aqueous sodium hydro-
gen carbonate solution and extracted with ethyl acetate. The ex-
tract was washed with brine, dried and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography with n-hexane/ethyl acetate (7:3, v/v) to give
3-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)
pyrrolidinylcarbonyl]thiazolidine (7.28 g, 81%) as a white solid.
To a solution of the above compound (7.27 g, 17.4 mmol) in tet-
rahydrofuran (110 mL) was added 1 mol/L tetra-n-butylammo-
nium fluoride in tetrahydrofuran (19.2 mL) under ice-cooling.
After stirring at room temperature for 1.5 h, the mixture was con-
centrated under reduced pressure. The residue was poured into
brine and extracted with chloroform. The extract was dried and
concentrated under reduced pressure. The residue was purified
The residue was purified by silica gel column chromatography with
chloroform/methanol (20:1, v/v) to give the title compound
(5.25 g, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): d 1.45,
1.43 (9H, s), 1.95–2.35 (2H, m), 2.95–3.23 (2H, m), 3.45–3.98
(3H, m), 4.30–5.77 (6H, m).
C
22H30N6OSꢁ2C4H4O4ꢁ0.8H2O: C, 53.53; H, 5.92; N, 12.48. Found: C,
53.56; H, 5.74; N, 12.10; LC–MS (ESI) m/z 427.2 [M+H]+.
4.1.36. 3-{(2R,4R)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-
yl)piperazin-1-yl]pyrrolidin-2-yl-carbonyl}thiazolidine
dimaleate (8s)
The title compound was prepared in 49% yield using 12d and 3-
((R)-1-tert-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl)thiazoli-
dine in the procedures outlined for 8n. Mp: 166–167 °C; 1H NMR
(300 MHz, DMSO-d6): d 1.66 (1H, m), 2.15 (3H, s), 2.51–2.54 (5H,
m), 2.64–2.79 (5H, m), 3.02–3.14 (4H, m), 3.41 (1H, m), 3.60–
3.90 (2H, m), 4.42–4.71 (3H, m), 5.80 (1H, s), 6.16 (4H, s), 7.28
(1H, t, J = 7.3 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.73 (2H, d, J = 7.3 Hz);
Anal. Calcd for C22H30N6OSꢁ2C4H4O4: C, 54.70; H, 5.81; N, 12.76.
Found: C, 54.61; H, 5.78; N, 12.68.
4.1.37. 1-Benzyloxycarbonylisonipecotic acid anilide (14)
To a solution of 1-benzyloxycarbonylisonipecotic acid (13,
13.1 g, 49.8 mmol), aniline (5.15 g, 54.7 mmol) and HOBt (11.4 g,
74.4 mmol) in tetrahydrofuran (200 mL) was added EDC hydro-
chloride (11.4 g, 59.5 mmol). The reaction mixture was stirred at
room temperature for 17 h, and then concentrated under reduced
pressure. The residue wad poured into a saturated aqueous sodium
hydrogen carbonate solution and extracted with ethyl acetate. The
extract was washed with brine, dried and concentrated under re-
duced pressure to give the title compound (8.43 g, 50%) as a
pale-yellow oil. 1H NMR (300 MHz, CDCl3): d 1.61–2.06 (4H, m),
2.44–2. 56 (1H, m), 2.77–3.02 (2H, m), 4.03–4.36 (2H, m), 5.14
(2H, s), 7.11 (1H, t, J = 7.4 Hz), 7.20–7.44 (7H, m), 7.50 (2H, d,
J = 7.9 Hz).
4.1.35. 3-{(2S,4R)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-
yl)piperazin-1-yl]pyrrolidin-2-yl-carbonyl}thiazolidine
dimaleate (8r)
To
a solution of 24 (2.88 g, 9.52 mmol) and 2,6-lutidine
(1.22 mL, 10.5 mmol) in dichloromethane (50 mL) was added a
solution of trifluoromethanesulfonic anhydride (2.95 g, 10.5 mmol)
in dichloromethane (5 mL) dropwise under ice-cooling over
10 min. The mixture was stirred for 30 min and 12d (2.10 g,
8.67 mmol) and diisopropylethylamine (3.6 mL, 21 mmol) were
added to the solution. After stirring at room temperature at 21 h,
the reaction mixture was poured into a saturated aqueous sodium
hydrogen carbonate solution and extracted with chloroform. The
extract was washed with brine, dried and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography with chloroform/methanol (30:1, v/v) to give 3-
{(2S,4R)-1-(tert-butoxycarbonyl)-4-[4-(3-methyl-1-phenyl-1H-
pyrazol-5-yl)piperazin-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazoli-
dine (2.70 g, 54%) as a amorphous. 1H NMR (300 MHz, CDCl3): d
4.1.38. 4-(1-Phenyl-1H-tetrazol-5-yl)piperidine (15)
To a solution of 14 (2.00 g, 5.91 mmol), triphenylphosphine
(3.10 g, 11.8 mmol) and a 40% diisopropyl azodicarboxylate–tolu-
ene solution (6.00 g, 11.9 mmol) in tetrahydrofuran (50 mL) was
added trimethylsilylazide (1.57 mL, 11.8 mmol) under ice-cooling.
The mixture was stirred at room temperature for 5 days, and then
concentrated under reduced pressure. The residue was purified by
silica gel chromatography with n-hexane/ethyl acetate (1:1, v/v) to
give
1-benzyloxycarbonyl-4-(1-phenyl-1H-tetrazol-5-yl)piperi-
dine (4.09 g) as a brown oil.
To a solution of the above compound (4.09 g) in methanol
(50 mL) was added 10% palladium/carbon (420 mg). The resulting
mixture was stirred at room temperature under a hydrogen