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D. D. Staas et al. / Bioorg. Med. Chem. 14 (2006) 6900–6916
J = 2.5 Hz, 1H), 7.57 (dd, J = 2.0, 8.5 Hz, 1H), 7.50 (d,
J = 8.5 Hz, 1H), 4.33–4.30 (m, 3H), 4.20 (d,
J = 15.5 Hz, 1H), 3.83–3.78 (m, 1H), 3.66–3.61 (m,
1H), 2.25–2.18 (m, 1H), 2.11–1.99 (m, 3H), 1.93–1.87
(m, 1H), 1.49 (dd, J = 8.2, 14.8 Hz, 1H), 1.16 (s, 3H),
0.49–0.42 (m, 2H), 0.39–0.35 (m, 1H), 0.32–0.29 (m,
1H). HRMS (APCI): calcd for (C20H27ClN7O2)+,
432.1909; found: 432.1905.
(s, 3H), 0.48–0.29 (m, 4H). HRMS (ESI): calcd for
(C21H26ClF2N6O2)+, 467.1769; found: 467.1760.
6.33. 3-(1-Methylcyclopropyl)-D-alanyl-N-[5-chloro-2-
(1H-tetrazol-1-yl)benzyl]-4,4-difluoroprolinamide (44)
Compound 44 was prepared from Boc-3-(1-methylcy-
clopropyl)-D-alanine 6 (61 mg, 0.15 mmol) and N-[5-
chloro-2-(1H-tetrazol-1-yl)benzyl]-4,4-difluoroprolinamide
36 (91 mg, 0.24 mmol) according to general procedure
6.25 and was isolated as the bis-trifluoroacetate salt,
a fluffy white solid after lyophilization (71 mg, 70%).
LCMS tR = 1.25 min. 1H NMR (400 MHz, CD3OD):
d 9.52 (s, 1H), 8.76–8.75 (m, 1H), 7.73 (d, J = 2.0 Hz,
1H), 7.57 (dd, J = 2.0, 8.4 Hz, 1H), 7.51 (d,
J = 8.4 Hz, 1H), 4.54 (dd, J = 6.4, 9.2 Hz, 1H), 4.39–
4.33 (m, 1H), 4.28–4.03 (br m, 4H), 2.86–2.74 (m,
1H), 2.48–2.36 (m, 1H), 2.04 (dd, J = 6.0, 14.4 Hz,
1H), 1.50 (dd, J = 8.2, 14.4 Hz, 1H), 1.16 (s, 3H),
0.51–0.29 (br m, 4H). HRMS (APCI): calcd for
(C20H25ClF2N7O2)+, 468.1721; found: 468.1723.
6.30. 3-(1-Methylcyclopropyl)-D-alanyl-(4R)-N-[5-chloro-
2-(1H-1,2,4-triazol-1-yl)benzyl]-4-fluoro prolinamide
(41)
Compound 41 was prepared from Boc-3-(1-methylcy-
clopropyl)-D-alanine 6 (33 mg, 0.14 mmol) and (4R)-
N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4-fluoropro-
linamide 33 (60 mg, 0.14 mmol) according to general
procedure 6.25 and was isolated as the trifluoroace-
tate salt (42 mg, 55% yield). LCMS tR = 1.12 min.
1H NMR (400 MHz, CD3OD): d 8.79 (s, 1H), 8.21
(s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4,
8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 5.38 (br d,
J = 52.4 Hz, 1H), 4.47–4.38 (m, 2H), 4.26–4.20 (m,
2H), 4.03–3.83 (m, 2H), 2.59–2.51 (m, 1H), 2.18–
1.97 (m, 2H), 1.52 (dd, J = 8.0, 14.8, 1H), 1.14 (s,
3H), 0.49–0.29 (m, 4H). HRMS (ESI): calcd for
(C21H27ClFN6O2)+, 449.1868; found: 449.1855.
6.34. 3-(1-Chlorocyclopropyl)alanyl-(4R)-N-[5-chloro-2-
(1H-1,2,4-triazol-1-yl)benzyl]-4-fluoro prolinamides (45a
and 45b)
A
mixture
of
(2R)-2-azido-3-(1-chlorocyclopro-
pyl)propanoic acid 13 (105 mg, 0.56 mmol), (4R)-N-
[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4-fluoroprolina-
mide 33 (200 mg, 0.56 mmol, 1.0 equiv), EDC
(160 mg, 0.83 mmol, 1.5 equiv), and HOAT (38 mg,
0.28 mmol, 0.5 equiv) in DMF (1 mL) was brought
6.31. 3-(1-Methylcyclopropyl)-D-alanyl-(4S)-N-[5-chloro-
2-(1H-1,2, 4-triazol-1-yl)benzyl]-4-fluoro-L-prolinamide
(42)
Compound 42 was prepared from Boc-3-(1-methylcy-
clopropyl)-D-alanine 6 (30 mg, 0.12 mmol) and (4S)-
N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4-fluoropro-
linamide 34 (49 mg, 0.12 mmol) according to general
procedure 6.25 and was isolated as the bis-trifluoroac-
etate salt (white powder, 28 mg, 34% yield). LCMS
to pH 8 by dropwise addition of Hunig’s base and
¨
stirred at room temperature for 18 h. The solvent
was removed in vacuo. Purification by reverse-phase
chromatography [95:5 water (+0.1% TFA)/CH3CN
(+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN
(+0.1% TFA)] afforded an oil. The product was dis-
solved in EtOAc, and the solution was washed with
saturated aqueous NaHCO3 solution. The aqueous
layer was extracted twice into EtOAc. The organic
layers were combined, dried over Na2SO4, and con-
centrated in vacuo to afford (4R)-1-[(2R)-2-azido-3-
(1-chlorocyclopropyl)propanoyl]-N-[5-chloro-2-(1H-1,2,
4-triazol-1-yl)benzyl]-4-fluoro-L-prolinamide as the free
base (156 mg, 57%). LCMS tR = 1.91 min. 1H NMR
(400 MHz, CDCl3): d 8.74 (s, 1H), 8.32 (s, 1H), 7.60
(d, J = 2 Hz, 1H), 7.43 (dd, J = 2.0, 8.4 Hz, 1H),
7.29 (d, J = 8.8 Hz, 1H), 5.34 (br d, J = 52.4 Hz,
1H), 4.64 (app t, J = 8.0 Hz, 1H), 4.32 (d,
J = 6.0 Hz, 2H), 4.25 (dd, J = 6.0, 7.6 Hz, 1H), 4.16–
4.08 (m, 1H), 3.83–3.71 (m, 1H), 2.66–2.06 (m, 3H),
2.05–1.98 (m, 1H), 1.20–0.77 (m, 4H). MS (ESI):
495.3 (M+H)+. A solution of this material (156 mg,
0.32 mmol) in THF (2 mL) at 0 ꢁC was treated with
triphenylphosphine (87 mg, 0.33 mmol, 1.05 equiv).
After stirring for 1 h at 0 ꢁC, water (114 lL,
6.30 mmol, 20 equiv) was added. The reaction mixture
was warmed to 40 ꢁC for 2 h then allowed to stir at
25 ꢁC for 66 h. The solvent was removed in vacuo,
and the residue was purified by reverse-phase chroma-
tography [95:5 water (+0.1% TFA)/CH3CN (+0.1%
TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1%
tR = 1.13 min. 1H NMR (400 MHz, CD3OD):
d
8.77(s, 1H), 8.21 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H),
7.47 (dd, J = 2.0, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz,
1H), 5.37 (br d, J = 53.4 Hz, 1H), 4.59 (d,
J = 10.0 Hz, 1H), 4.38–4.10 (m, 4H), 3.99–3.87 (m,
1H), 2.60–2.33 (m, 2H), 2.11–2.06 (m, 1H), 1.50–1.41
(m, 1H), 1.16 (s, 3H), 0.50–0.27 (m, 4H). HRMS
(APCI): calcd for (C21H27ClFN6O2)+, 449.1868; found:
449.1857.
6.32. 3-(1-Methylcyclopropyl)-D-alanyl-N-[5-chloro-2-
(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro prolinamide
(43)
Compound 43 was prepared from Boc-3-(1-methylcy-
clopropyl)-D-alanine 6 (30 mg, 0.12 mmol) and N-[5-
chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoropro-
linamide 35 (51 mg, 0.12 mmol) according to general
procedure 6.25 and was isolated as the bis-trifluoroace-
tate salt (white powder, 31 mg, 37% yield). LCMS
tR = 1.26 min. 1H NMR (400 MHz, CD3OD): d 8.77
(s, 1H), 8.21 (s, 1H), 7.64 (s, 1H), 7.50–7.43 (m, 2H),
4.85–4.55 (m, 1H), 4.43–4.37 (m, 1H), 4.28–4.15 (m,
3H), 4.08–4.03 (m, 1H), 2.83–2.77 (m, 1H), 2.45–2.40
(m, 1H), 2.06–2.01 (m, 1H), 1.53–1.47 (m, 1H), 1.14