494 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Berger et al.
1.73 (dt, 1H, J1 ) 9 Hz, J2 ) 12 Hz), 2.39 (t, 2H, J ) 7.2 Hz),
2.9 (m, 1H), 3.32 (m, 1H), 3.4 (dd, 1H), 3.52 (dd, 1H, J1 ) 7.2
Hz, J2 ) 13.2 Hz), 3.69 (dd, 1H, J1 ) 7.2 Hz, J2 ) 13.2 Hz),
4.15 (m, 1H), 5.74 (s, 1H), 7.17-7.34 (m, 9H), 7.47 (m, 6H),
8.1 (s, 2H); MS m/z 496 (M + H+).
was evaporated under reduced pressure and dissolved in THF
(100 mL). 2-Naphthalenesulfonyl chloride (49.9 g, 220 mmol)
in THF (200 mL) was added slowly and the mixture was
stirred at room temperature for 16 h. Water (150 mL) was
added and after 1 h the solvents were evaporated. The residue
was partitioned between water/ethyl acetate (3×), the organic
phases were washed with 10% NaCl and dried (Na2SO4) to
give 30 (60.4 g, 82%): IR (ATR microscope) 3509, 1729, 1337,
(2S,4R)-2-[1-(5-Propylpyrimidin-2-yl)-4-tritylsulfa-
nylpyrrolidin-2-ylmethyl]isoindole-1,3-dione (25). Tri-
phenyl phosphine (764 mg, 2.82 mmol) and phthalimide (420
mg, 2.82 mmol) were added to a solution of 24 (1.0 g, 2.0 mmol)
in THF (15 mL) at room temperature. The reaction mixture
was cooled to 0 °C and diethylazo dicarboxylate (615 µL, 3.83
mmol) in THF (3 mL) was added. The solution was stirred at
room temperature overnight, H2O was added, and the inor-
ganic layer was extracted with ethyl acetate. The combined
layers were washed with 1 M NaOH, a saturated solution of
NaHCO3, and brine and dried (Na2SO4). Column chromatog-
raphy with ethyl acetate/n-hexane 1:2 as eluent yielded 25
(1.20 g, 95%) as a white solid: IR (ATR microscope) 1711, 1144,
1
1238, 1197, 1026 cm-1; H NMR (CDCl3) δ 1.48 (d, 1H, J ) 6
Hz), 2.12 (m, 1H), 2.22 (m, 1H), 3.47 (dt, 1H, J ) 12 Hz), 3.66
(dd, 1H, J1 ) 4.8 Hz, J2 ) 12 Hz), 3.74 (s, 3H), 4.46 (m, 1H),
4.53 (t, 1H, J ) 9 Hz), 7.64 (m, 2H), 7.9 (m, 2H), 7.99 (m, 2H),
8.47 (s, 1H); MS m/z 335 (M+).
(2S,4S)-4-Methanesulfonyloxy-1-(naphthalene-2-sulfo-
nyl)pyrrolidine-2-carboxylic Acid Methyl Ester (31). A
solution of 30 (34.5 g, 120.8 mmol) in toluene (250 mL) and
THF (150 mL) was added to a suspension of methanesulfonic
acid (8 mL, 123.4 mmol), triethylamine (17.2 mL, 123.4 mmol),
and triphenylphosphine (33.7 g, 128.5 mmol) in toluene (150
mL). After the addition of diethyl azodicaboxylate (20.8 mL,
133.6 mmol), the solution was heated to 80 °C for 3 h and
stirred at room temperature overnight. The reaction mixture
was diluted with ethyl acetate (350 mL), and water (250 mL)
was added. The phases were separated, and the inorganic
phase was extracted with ethyl acetate (3 × 300 mL). The
organic phase was washed with aqueous 1 M KHSO4 and
brine, dried (Na2SO4), and evaporated. Column chromatogra-
phy gave 31 (37.5 g, 88%) as a colorless solid: IR (ATR
1
742, 697 cm-1; H NMR (CDCl3) δ 0.78 (t, 3H), 1.37 (m, 2H),
1.54 (dd, 1H, J1 ) 7.2 Hz, J2 ) 12 Hz), 1.8 (m, 1H), 2.19 (t,
2H), 3.06 (m, 1H), 3.27 (t, 1H), 3.45 (dd, 1H, J1 ) 9.2 Hz, J2 )
10 Hz), 3.61 (m, 2H), 4.58 (m, 1H), 7.16-7.33 (m, 9H), 7.40
(dd, 6H), 7.58-7.90 (m, 6H); MS m/z 625 (M + H+).
(2S,4R)-[[1-(5-Propylpyrimidin-2-yl)-4-tritylsulfanylpyr-
rolidin-2-yl]methyl]amine (26). 25 (960 mg, 1.54 mmol) in
ethanol (95 mL) was treated with hydrazine hydrate (2.4 mL,
49.4 mmol) under reflux. After cooling to room temperature,
the solution was filtered and concentrated, and the crude
product was purified by flash chromatography with dichlo-
romethane/methanol/NH4OH 90:10:0.25 to yield 26 (659 mg,
88%) as a white foam: IR (ATR microscope) 1600, 1486, 1443,
1
microscope) 1747, 1600, 1333, 1184, 821, 751 cm-1; H NMR
(CDCl3) δ 2.35 (m, 1H), 2.56 (dd, 1H, J ) 13.2 Hz), 2.96 (s,
3H), 3.71 (s, 3H), 3.74 (m, 2H), 4.67 (dd, 1H, J1 ) 3.6 Hz, J2 )
9 Hz), 5.17 (m, 1H), 7.66 (m, 2H), 7.91 (dt, 2H), 8.0 (d, 2H),
8.47 (s, 1H); MS m/z 414 (M + H+).
740, 696 cm-1 1H NMR (CDCl3) δ 0.92 (t, 3H, J ) 7.2 Hz),
;
1.17 (dd, 1H, J1 ) 6 Hz, J2 ) 13.2 Hz), 1.47-1.76 (m, 3H),
1.55 (m, 1H), 2.33 (m, 1H), 2.37 (m, 2H), 2.70 (dd, 1H, J1 )
4.8 Hz, J2 ) 13.2 Hz), 2.95 (m, 1H), 3.39 (t, 1H, J ) 12 Hz),
3.77 (dd, 1H, J1 ) 7.2 Hz, J2 ) 12 Hz), 3.95 (m, 2H), 7.19-
7.38 (m, 9H), 7.49 (m, 6H), 8.11 (s, 2H); MS m/z 495 (M +
H+).
(2S,4R)-4-(4-Methoxybenzylsulfanyl)-1-(naphthalene-
2-sulfonyl)pyrrolidine-2-carboxylic Acid Methyl Ester
(32). Potassium tert-butylate (157 mg, 1.4 mmol) in DMF (5
mL) was treated with 4-methoxybenzylmercaptane (0.2 mL,
1.4 mmol) at 0°C. The solution was stirred at room tempera-
ture for 20 min before 31 (532 mg, 1.3 mmol) in DMF (5 mL)
was added. The reaction was stirred at 100 °C for 1 h and
cooled to room temperature, and a saturated solution of NH4-
Cl was added. The layers were separated, and the inorganic
phase was extracted with ethyl acetate, washed with a solution
of NaHCO3 and brine, dried (Na2SO4), and evaporated. The
crude oil was purified by flash chromatography on silica gel
with hexane/ethyl acetate (2:1) as eluent to yield 32 (295 mg,
48%) as a colorless oil: 1H NMR (CDCl3) δ 1.93 (dt, 1H, J1 )
8.4 Hz, J2 ) 12 Hz), 2.19 (m, 1H), 3.18 (dd, 1H, J1 ) 6.6 Hz,
J2 ) 11.4 Hz), 3.29 (m, 1H), 3.55 (s, 2H), 3.70 (s, 3H), 3.74 (m,
1H), 3.77 (s, 3H), 4.41 (dd, 1H, J1 ) 4.8 Hz, J2 ) 7.2 Hz), 6.78
(d, 2H), 7.07 (d, 2H), 7.65 (m, 2H), 7.84 (dd, 1H), 7.94 (m, 1H),
7.99 (m, 2H), 8.41 (s, 1H); MS m/z 472 (M + H+).
(2S,4R)-(2,5-Difluorobenzyl)-[1-(5-propylpyrimidin-2-
yl)-4-tritylsulfanylpyrrolidin-2-ylmethyl]amine (27). 2,5-
Difluorobenzaldehyde (158 µL, 1.43 mmol) and methanol (5
mL) were added to 26 (643 mg, 1.3 mmol) in methanol (3 mL)
to partially dissolve the compound, followed by a solution of
zinc chloride (108 mg, 0.78 mmol) and NaBH3CN (109 mg, 1.56
mmol) in methanol (3 mL). The solution was stirred overnight
and concentrated, and the residue was dissolved in ethyl
acetate/saturated NaHCO3. The inorganic layer was extracted
with ethyl acetate, and the combined organic layers were
washed with a solution of NaHCO3 and brine, dried (Na2SO4),
and evaporated. Purification with column chromatography
yielded 27 (750 mg, 93%) as a light yellow gum: IR (ATR
microscope) 3330, 1600, 1443, 840, 740, 696 cm-1 1H NMR
;
(CDCl3) δ 0.91 (t, 3H),1.33 (m, 2H), 1.55 (m, 2H), 1.73 (m, 1H),
2.30 (dd, 1H), 2.36 (t, 2H), 2.64 (dd, 1H), 3.0 (m, 1H), 3.36 (t,
1H), 3.64 (s, 2H), 3.68 (m, 1H), 4.11 (m, 1H), 6.79-7.02 (m,
3H), 7.15-7.33 (m, 9H), 7.48 (m, 6H), 8.1 (s, 2H); MS m/z 621
(M + H+).
(2S,4R)-4-(4-Methoxybenzylsulfanyl)-1-(naphthalene-
2-sulfonyl)pyrrolidine-2-carboxylic Acid (33). At 0 °C, 0.1
M LiOH (950 mL, 95 mmol) was added to a solution of 32 (14.8
g, 31.6 mmol) in THF (950 mL). The solution was stirred at
room temperature for 2 h and diluted with ice-cold water. Then
1 M KHSO4 was added (pH 2), and the inorganic phase was
extracted with ethyl acetate. The combined organic phases
were washed with brine, dried (Na2SO4), and evaporated. The
product was crystallized from ethyl acetate/n-hexane to yield
33 (13.15 g, 90%) as a colorless solid: 1H NMR (CDCl3) δ 1.89
(dt, 1H, J1 ) 9 Hz, J2 ) 12 Hz), 2.31 (m, 1H), 3.13 (dd, 1H, J1
) 6 Hz, J2 ) 9 Hz), 3.29 (m, 1H), 3.55 (s, 3H), 3.76 (m, 1H),
3.77 (s, 3H), 4.4 (dd, 1H, J1 ) 4.8 Hz, J2 ) 7.2 Hz), 6.79 (d,
2H, J ) 7.2 Hz), 7.13 (d, 2H, J ) 7.2 Hz), 7.67 (m, 2H), 7.84
(dd, 1H), 7.94 (dd, 1H), 8.01 (dd, 2H), 8.44 (s, 1H); MS m/z
456 (M-H-).
(2S,4R)-5-[(2,5-Difluorobenzylamino)methyl]-1-(5-pro-
pylpyrimidin-2-yl)pyrrolidine-3-thiol (28). As described for
12, compound 28 was prepared from 27, as a colorless gum:
IR (ATR microscope) 3305, 2470, 1603, 1541, 1494, 874 cm-1
;
1H NMR (CDCl3) δ 0.93 (t, 3H, J ) 7.4 Hz), 1.57 (m, 2H), 1.64
(m, 1H), 1.69 (d, 1H, J ) 7.2 Hz), 2.05 (dt, 1H, J1 ) 8.4 Hz, J2
) 12 Hz), 2.39 (t, 2H, J ) 7.8 Hz), 2.45 (m, 1H), 2.77 (dd, 1H,
J1 ) 6 Hz, J2 ) 12 Hz), 2.9 (dd, 1H, J1 ) 4.8 Hz, J2 ) 13.2
Hz), 3.49 (dd, 1H, J1 ) 6 Hz, J2 ) 12 Hz), 3.64 (m, 1H), 3.83
(s, 2H), 3.97 (dd, 1H, J1 ) 6 Hz, J2 ) 12 Hz), 4.36 (m, 1H),
6.82-7.02 (m, 2H), 7.15 (m, 1H), 8.14 (s, 2H); MS m/z 379 (M
+ H+). Anal. (C19H24F2N4S) C, H, N, S, F.
(2S,4R)-4-(4-Methoxybenzylsulfanyl)-1-(naphthalene-
2-sulfonyl)pyrrolidine-2-carboxylic Acid N′-Methylhy-
drazide (34). At 0 °C, N-hydroxy-2-pyridone (0.26 g, 2.7 mmol)
was added to a solution of 33 (1 g, 2.1 mmol) in dichlo-
romethane (10 mL), followed by N,N-dicyclohexylcarbodiimide
(0.48 mg, 2.3 mmol) in dichloromethane (10 mL) over a period
(2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)pyrroli-
dine-2-carboxylic Acid Methyl Ester (30). 29 (40 g, 220
mmol, twice suspended in toluene and evaporated under
reduced pressure to remove water) was suspended in hexa-
methyldisilazane (600 mL) and refluxed for 2 h. The solution