4130 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 25
Ogilvie et al.
phase using the trifluoromethyl ketone resin (Scheme 3).
Final purification was performed by preparative HPLC: IR
(KBr) 1638 cm-1; 1H NMR (DMSO-d6) 1:1 mixture of diaster-
eomers at P1, δ 8.56-8.49 (m, 0.1H), 8.10-8.03 (m, 0.8H),
7.89-7.86 (m, 0.8H), 7.73-7.70 (m, 0.8H), 7.44-7.41 (m, 1H),
6.95-6.80 (m, 1.5H), 4.63-4.54 (m, 1H), 4.20-4.06 (m, 3H),
2.94-2.93 (m, 3H), 2.80-2.78 (m, 3H), 2.67-2.62 (m, 2H),
1.99-1.93 (m, 2H), 1.87-1.86 (m, 3H), 1.30-1.25 (m, 0.5H),
1.07-1.06 (m, 2.5H), 0.84-0.83 (m, 12H); HRMS calcd for
C22H37F3N5O6 (MH+) 524.2696, found 524.2710.
N4,N4-Dim eth yl-N1-(3,3,3-tr iflu or o-1-m eth yl-2-oxop r o-
p yl)-(2S)-2-[[(1S)-1-[[(1S)-2-m eth yl-1-(m eth ylca r boxa m i-
d o ) p r o p y l ] c a r b o x a m i d o ] p r o p y l ] c a r b o x a m i d o ] -
bu ta n ed ia m id e (57). Final purification was performed by
preparative HPLC: IR (KBr) ν 3283, 1642 cm-1 1H NMR
;
(DMSO-d6) 2:1 mixture of hydrate/non-hydrate, 1:1 mixture
of diastereomers at P1, δ 8.05 and 8.01 (2 d, J ) 7.6 and 7.6
Hz, 1H), 7.91-7.82 (m, 2H), 7.43 and 7.39 (2 d, J ) 9.2 and
9.2 Hz, 1H), 7.01-6.80 (m, 2H), 4.61-4.52 (m, 1H), 4.22-4.00
(m, 3H), 2.94 and 2.93 (2 s, 3H), 2.80 (s, 3H), 2.71-2.59 (m,
2H), 2.00-1.90 (m, 1H), 1.87 and 1.86 (2 s, 3H), 1.73-1.61
(m, 1H), 1.57-1.45 (m, 1H), 1.06 (d, J ) 6.0 Hz, 3H), 0.87-
0.78 (m, 9H); HRMS calcd for C21H35F3N5O6 (MH+) 510.2539,
found 510.2526.
N1-(3,3,3-Tr iflu or o-1-m eth yl-2-oxop r op yl)-(2S)-4-m eth -
yl-2-[[(1S)-2-m eth yl-1-[[(1S)-2-m eth yl-1-(m eth ylca r boxa -
m i d o )p r o p y l]c a r b o x a m i d o ]p r o p y l]c a r b o x a m i d o ]-
p en ta n a m id e (52). This compound was prepared on solid
phase using the trifluoromethyl ketone resin (Scheme 3).
Final purification was performed by preparative HPLC: IR
N4,N4-Dim eth yl-N1-(3,3,3-tr iflu or o-1-m eth yl-2-oxop r o-
p yl)-(2S)-2-[[(1S)-2,2-d im eth yl-1-[[(1S)-2-m eth yl-1-(m eth -
y l c a r b o x a m i d o ) p r o p y l ] c a r b o x a m i d o ] p r o p y l ] -
ca r boxa m id o]bu ta n ed ia m id e (58). Final purification was
performed by preparative HPLC: IR (KBr) ν 3500-2900, 1640,
(KBr) ν 3268, 3080, 1632 cm-1 1H NMR (DMSO-d6) 1:1.2
;
hydrate/non-hydrate, 1.2:1 mixture of diastereomers at P1, δ
8.72 (d, J ) 6.5 Hz, 0.25H), 8.70 (d, J ) 6.5 Hz, 0.3H), 7.91-
8.10 (m, 1H), 7.84-7.88 (m, 1H), 7.74-7.80 (m, 1H), 7.55 (d,
J ) 8.6 Hz, 0.2H), 7.53 (d, J ) 8.9 Hz, 0.25H), 6.90-6.96 (m,
1H), 4.57-4.68 (m, 0.5H), 4.26-4.39 (m, 1H), 4.15-4.21 (m,
1H), 4.05-4.14 (m, 1.4H), 1.87-1.95 (m, 2H), 1.85 (s, 3H),
1.53-1.63 (m, 1H), 1.30-1.50 (m, 2H), 1.26 (d, J ) 7.0 Hz,
0.8H), 1.25 (d, J ) 7.0 Hz, 1H), 1.07 (d, J ) 6.7 Hz, 0.8H),
1.06 (d, J ) 6.7 Hz, 0.6H), 0.78-0.88 (m, 18H); HRMS calcd
for C22H38F3N4O5 (MH+) 495.2794, found 495.2803.
1538 cm-1 1H NMR (DMSO-d6) hydrated form only, 1:1
;
mixture of diastereomers at P1, δ 8.20 and 8.13 (d, J ) 7.4
and 7.2 Hz, 1H), 7.91 and 7.91 (d, J ) 9.0 and 8.7 Hz, 1H),
7.56 and 7.55 (d, J ) 9.3 and 9.3 Hz, 1H), 7.50 and 7.43 (d, J
) 9.3 and 9.3 Hz, 1H), 6.93 (br s, 1H), 6.81 (br s, 1H), 4.57 (m,
1H), 4.23 (m, 2H), 4.11 (m, 1H), 2.95 and 2.94 (s, 3H), 2.80
and 2.80 (s, 3H), 2.72-2.57 (m, 2 H), 1.95 (m, J ) 6.9 Hz, 1H),
1.87 (s, 3H), 1.07 and 1.06 (d, J ) 8.1 and 6.6 Hz, 3H), 0.89 (s,
9H), 0.83 (d, J ) 6.8 Hz, 6H); HRMS calcd for C23H39F3N5O6
(MH+) 538.2852, found 538.2843.
N1-[(1S)-2-Meth yl-1-[[(1S)-2-p h en yl-1-[(3,3,3-tr iflu or o-
1-m e t h yl-2-oxop r op yl)ca r b a m oyl]e t h yl]ca r b a m oyl]-
p r op yl]-(2S)-3-m et h yl-2-(m et h ylca r b oxa m id o)b u t a n a -
m id e (53). This compound was prepared by solid phase using
the trifluoromethyl ketone resin (Scheme 3). Final purification
was performed by preparative HPLC: IR (KBr) ν 3280, 1636,
N4,N4-Dim eth yl-N1-(3,3,3-tr iflu or o-1-m eth yl-2-oxop r o-
p yl)-(2S)-2-[[(1S)-3,3-d im eth yl-1-[[(1S)-2-m eth yl-1-(m eth -
ylcar boxam ido)pr opyl]car boxam ido]bu tyl]car boxam ido]-
bu ta n ed ia m id e (59). Final purification was performed by
1
1546 cm-1; H NMR (DMSO-d6) 3:1 hydrate/non-hydrate, 1:1
preparative HPLC: IR (KBr) ν 3285, 1644 cm-1 1H NMR
;
mixture of diastereomers at P1, δ 8.79 (d, J ) 5.7 Hz, 0.12H),
8.71 (d, J ) 6.4 Hz, 0.12H), 8.03 (m, 1H), 7.86 (m, 1H), 7.64
(m, 1.76H), 7.22 (m, 5H), 6.93 and 6.90 (2 d, J ) 14.3 and 13.7
Hz, 1.6H), 4.63-4.54 (m, 1.25H), 4.16-4.05 (m, 2.75H), 3.00-
2.66 (m, 2H), 1.86 (s, 3H), 1.85 (m, 2H), 1.25, 1.21, 1.09 and
0.96 (4 d, J ) 7.4, 6.8, 6.9 and 7.9 Hz, 3H), 0.79 (m, 12H);
HRMS calcd for C25H36F3N4O5 (MH+) 529.2638, found 529.2619.
N1-[(1S)-2-Meth yl-1-[[(1S)-2-m eth yl-1-[(3,3,3-tr iflu or o-
1-m et h yl-2-oxop r op yl)ca r b a m oyl]p r op yl]ca r b a m oyl]-
p r op yl]-(2S)-3-m et h yl-2-(m et h ylca r b oxa m id o)b u t a n a -
m id e (54). Final purification was performed by preparative
HPLC: IR (KBr) 1633 cm-1; 1H NMR (DMSO-d6) 1:1 mixture
of diastereoisomers at P1, δ 8.78 (d, J ) 5.5 Hz, 0.25H), 8.71
(d, J ) 5.5 Hz, 0.25H), 7.88-7.60 (m, 3.5H), 6.98-6.87 (m,
1H), 4.70-4.64 (m, 0.5H), 4.22-4.09 (m, 3.5H), 1.97-1.91 (m,
3H), 1.86 (s, 3H), 1.28-1.26 (m, 1.7H), 1.09-1.07 (m, 1.3H),
0.88-0.78 (m, 18H); FAB MS m/z 481 (MH+); HRMS calcd for
C21H36F3N4O5 (MH+) 481.2638, found 481.2627.
(DMSO-d6) 16:1 mixture of hydrate/non-hydrate, 3:2 mixture
of diastereomers at P1, δ 8.05 (d, J ) 8.3 Hz, 1H), 7.91-7.79
(m, 2H), 7.43 and 7.39 (2 d, J ) 9.2 and 9.2, 1H), 7.11-6.66
(br s, 2H hydrate), 4.62-4.49 (m, 1H), 4.36-4.25 (m, 1H),
4.16-4.02 (m, 2H), 2.94 and 2.93 (2 s, 3H), 2.80 (s, 3H), 2.71-
2.55 (m, 2H), 1.99-1.88 (m, 1H), 1.85 and 1.84 (2 s, 3H), 1.67-
1.58 (m, 1H), 1.46 (dd, J ) 14.2 and 8.9 Hz, 1H), 1.28-1.25
(m, 0.2H), 1.06 (d, J ) 6.7 Hz, 2.8H), 0.86 (s, 9H), 0.83 (d, J )
6.7 Hz, 3H), 0.81 (d, J ) 6.7 Hz, 3H); HRMS calcd for
C
24H41F3N5O6 (MH+) 552.3009, found 552.3031.
N4,N4-Dim eth yl-N1-(3,3,3-tr iflu or o-1-m eth yl-2-oxop r o-
p yl)-(2S )-2-[[(S )-1-(1-a d a m a n t yl)-1-[[(1S )-2-m e t h yl-1-
(m e t h y lc a r b o xa m id o)p r op yl]c a r b o xa m id o ]m e t h y l]-
ca r boxa m id o]bu ta n ed ia m id e (60). Final purification was
performed by preparative HPLC: IR (KBr) ν 3293, 1641, 1533
cm-1; 1H NMR (DMSO-d6) 4:1 mixture of hydrate/non-hydrate,
1:1 mixture of diastereomers at P1, δ 8.58 (d, J ) 5.5 Hz, 0.1H),
8.47 (d, J ) 6.5 Hz, 0.1H), 8.22-8.12 (m, 1H), 7.94-7.91 (m,
1H), 7.49-7.38 (m, 1.9H), 6.94 (br s, 1H), 6.86 (br s, 1H), 4.60-
4.52 (m, 1H), 4.24-4.20 (m, 1H), 4.13-3.98 (m, 2H), 2.94 (s,
1.5H), 2.93 (s, 1.5H), 2.79 (s, 3H), 2.74-2.57 (m, 2H), 2.00-
1.94 (m, 1H), 1.94-1.86 (m, 3H), 1.87 (s, 3H), 1.64-1.48 (m,
12H), 1.26-1.25 (m, 0.6H), 1.07 (d, J ) 6.5 Hz, 2.4H), 0.82 (d,
N1-[(1S)-2-Meth yl-1-[[(1S)-1-[(3,3,3-tr iflu or o-1-m eth yl-
2-oxop r op yl)ca r ba m oyl]eth yl]ca r ba m oyl]p r op yl]-(2S)-3-
m eth yl-2-(m eth ylca r boxa m id o)bu ta n a m id e (55). Final
purification was performed by preparative HPLC: IR (KBr) ν
3264, 1627, 1552 cm-1 1H NMR (DMSO-d6) 1:1 mixture of
;
diastereomers at P1, δ 7.98 and 7.92 (2 d, J ) 7.3 and 7.3 Hz,
1H), 7.88-7.83 (m, 1H), 7.72 (d, J ) 8.8 Hz, 1H), 7.58 (t, J )
9.4 Hz, 1H), 6.95 and 6.91 (2 br s, 2H), 4.33-4.06 (m, 4H),
1.95 (m, 2H), 1.87 (s, 3H), 1.17-1.13 (m, 3H), 1.08 (d, J ) 6.9
Hz, 3H), 0.85-0.81 (m, 12H); HRMS calcd for C19H32F3N4O5
(MH+) 453.2325, found 453.2338.
N1-[(1S)-2-Meth yl-1-[[(1R)-1-[(3,3,3-tr iflu or o-1-m eth yl-
2-oxop r op yl)ca r ba m oyl]eth yl]ca r ba m oyl]p r op yl]-(2S)-3-
m eth yl-2-(m eth ylca r boxa m id o)bu ta n a m id e (56). Final
purification was performed by preparative HPLC: IR (KBr)
1634 cm-1; 1H NMR (DMSO-d6) 1:1 mixture of diastereomers
at P1, δ 8.63 (d, J ) 5.5 Hz, 0.1H), 8.56 (d, J ) 4.5 Hz, 0.1H),
8.18-8.12 (m, 0.2H), 8.01 (d, J ) 7 Hz, 0.3H), 7.96 (d, J ) 7.5
Hz, 0.3H), 7.89-7.74 (m, 1.8H), 7.65 (d, J ) 9 Hz, 0.3H), 7.60
(d, J ) 9.5 Hz, 0.3H), 6.96-6.92 (m, 1.3H), 4.68-4.59 (m,
0.3H), 4.34-4.25 (m, 1H), 4.19-4.02 (m, 2.7H), 1.98-1.89 (m,
2H), 1.86 (s, 3H), 1.31-1.29 (m, 0.8H), 1.19-1.07 (m, 5.2H),
0.86-0.82 (m, 12H); HRMS calcd for C19H32F3N4O5 (MH+)
453.2325, found 453.2338.
J
) 6.5 Hz, 6H); HRMS calcd for
C
29H45F3N5O6 (MH+)
616.3322, found 616.3335.
(3S)-3-[[(1S)-2-(Dim eth ylca r ba m oyl)-1-[(3,3,3-tr iflu or o-
1-m eth yl-2-oxop r op yl)ca r ba m oyl]eth yl]ca r ba m oyl]-2,2-
dim eth yl-3-[[(1S)-2-m eth yl-1-(m eth ylcar boxam ido)pr opyl]-
ca r boxa m id o]p r op a n oic Acid (61). This compound was
prepared in solution using standard coupling methods. The
â,â-dimethylaspartic acid residue was incorporated as the
γ-benzyl ester derivative. Oxidation of the trifluoromethyl
alcohol was accomplished with the Dess-Martin periodinane.
Final purification was performed by preparative HPLC: IR
1
(KBr) ν 1654, 1532 cm-1; H NMR (DMSO-d6) 1:1 mixture of
diastereomers at P1, δ 7.98-7.89 (m, 2 H), 7.76 (d, J ) 7.5
Hz, 0.5H), 7.67 (d, J ) 7.5 Hz, 0.5H), 7.53 (d, J ) 9 Hz, 0.5H),
7.48 (d, J ) 9 Hz, 0.5H), 6.92 (br s, 1H), 6.83 (br s, 1H), 4.75
(d, J ) 9.5 Hz, 1H), 4.57-4.51 (m, 1H), 4.27-4.19 (m, 1H),
4.18-4.03 (m, 1H), 2.94 (s, 1.5H), 2.93 (s, 1.5H), 2.80 (s, 3H),
2.71-2.57 (m, 2H), 2.04-1.95 (m, 1H), 1.87 (s, 3H), 1.08-1.05