A.M. Said, D.G. Hangauer / European Journal of Medicinal Chemistry 96 (2015) 405e424
421
(m, 3H) 2.10e2.20 (m, 1H) 2.29e2.34 (m, 1H) 2.40e2.47 (m, 1H)
2.51e2.60 (m, 1H) 3.05e3.20 (m, 2H) 4.30e4.39 (m, 1H) 4.50 (m,
1H) 7.10e7.29 (m, 4H) 7.80 (s, 1H); m/z (LCMS, ESI): found 295.2
[MþH] þ; [C16H23ClN2O þ H]þ requires 295.1.
4.1.8.6. (S)-N-(4-cyanobenzyl)-1-(3-phenylpropyl)pyrrolidine-2-
carboxamide (14f). Following the general procedure for the reduc-
tive amination, compound 2 (250 mg, 1.09 mmol) TEA (150
mL,
1.09 mmol) and hydrocinnamaldehyde (146 mg, 1.09 mmol) were
dissolved in 10 mL DCE. After 2 h, NaBH (OAc)3 (346 mg, 1.63 mmol)
was added to the mixture and left for stirring for 5 h at room
temperature. The crude product was obtained as colorless viscous
4.1.8.2. (S)-N-(3-chlorobenzyl)-1-(3-phenylpropyl)pyrrolidine-2-
carboxamide(7f). Following the general procedure for the reductive
amination, compound 1 (178 mg, 0.74 mmol) TEA (100
mL,
oil (271 mg, 71%). 500 MHz, 1H NMR (CDCl3-d1):
d 1.60e1.80 (m,
0.74 mmol) and hydrocinnamaldehyde (100 mg, 0.74 mmol) were
dissolved in 10 mL DCE. After 2 h, NaBH (OAc)3 (237 mg, 1.11 mmol)
was added to the mixture and left for stirring for 5 h at room
temperature. The crude product was purified with reverse phase
HPLC to give the final product as pale yellow oil residue (108 mg,
4H) 1.82e1.85 (m, 1H) 2.19e2.20 (m, 1H) 2.28e2.31 (m,1H) 2.50 (m,
2H) 2.59e2.60 (m, 2H) 3.10 (s, 1H) 3.15 (s, 1H) 4.35 (m, 1H) 4.45 (m,
1H) 7.13 (d, J ¼ 8.0 Hz, 2H) 7.23e7.26 (m, 5H) 7.45 (d, J ¼ 8.0 Hz, 2H)
þ
7.90 (t, J ¼ 6.0 Hz, 1H); m/z (LCMS, ESI): found 348.4 [MþH]
;
[C22H25N3O þ H]þ requires 348.2.
41%). 500 MHz, 1H NMR (CDCl3-d1):
d 1.70e1.84 (m, 4H) 1.90e1.98
(m,1H) 2.18e2.20 (m,1H) 2.35 (m,1H) 2.50e2.70 (m, 4H) 3.10e3.20
(m, 2H) 4.40 (m, 2H) 7.14 (d, J ¼ 8.0 Hz, 1H) 7.20e7.30 (m, 3H) 7.80
(s, 1H); m/z (LCMS, ESI): found 357.2 [MþH] þ; [C21H25ClN2O þ H]þ
requires 357.2.
4.1.8.7. tert-butyl((R)-1-((S)-2-((4-cyanobenzyl)carbamoyl)pyrroli-
din-1-yl)butan-2-yl)carbamate (15b). Following the general proce-
dure for the reductive amination, compound 2 (229 mg, 1.0 mmol)
TEA (135 mL,1.0 mmol) and 6b (187 mg, 1.0 mmol) were dissolved in
10 mL DCE. After 2 h, NaBH (OAc)3 (318 mg, 1.5 mmol) was added to
the mixture and left for stirring for 5 h at room temperature. The
crude product was obtained as colorless oil (238 mg, 59%).
4.1.8.3. (S)-1-((R)-2-aminobutyl)-N-(3-chlorobenzyl)pyrrolidine-2-
carboxamide hydrochloride (9b). Following the general procedure
for the reductive amination, compound 1 (50 mg, 0.21 mmol) TEA
400 MHz, 1H NMR (CDCl3-d1):
d 0.70 (m, 3H) 1.0e1.4 (s, 9H)
(30
m
L, 0.21 mmol) and 6b (40 mg, 0.21 mmol) were dissolved in
1.50e1.75 (m, 3H) 1.90e2.10 (m, 1H) 2.22 (m, 1H) 2.31e2.45 (m, 2H)
2.61 (m, 1H) 3.0e3.10 (m, 1H) 3.21 (m, 1H) 3.44 (m, 1H) 4.23e4.50
(m, 3H) 7.20 (m, 2H) 7.43 (m, 2H) 8.0 (t, J ¼ 6.4 Hz, 1H); m/z (LCMS,
ESI): found 423.2 [MþNa] þ; [C22H32N4O3 þ Na]þ requires 423.2.
10 mL DCE. After 2 h, NaBH (OAc)3 (68 mg, 0.32 mmol) was added to
the mixture and left for stirring for 5 h at room temperature. The
product 8b was dissolved in 3 N methanolic HCl (3 mL) and stirred
for 3 h. The crude product was further purified by reverse phase
HPLC to give the final product as white solid (30 mg, 62%). 500 MHz,
4.1.8.8. tert-butyl((R)-1-((S)-2-((4-cyanobenzyl)carbamoyl)pyrroli-
din-1-yl)-3-phenylpropan-2-yl) carbamate (15f). Following the
general procedure for the reductive amination, compound 2
1H NMR (CD3OD):
d
1.00 (t, J ¼ 7.5 Hz, 3H) 1.59e1.70 (m, 2H)
1.82e1.95 (m, 3H) 2.20e2.35 (m, 1H) 2.40 (s, 1H) 2.61e2.75 (m, 1H)
2.80 (s, 1H) 2.90 (s, 1H) 3.20e3.42 (m, 2H) 4.35e4.55 (m, 2H)
(229 mg, 1.0 mmol) TEA (135 mL, 1.0 mmol) and 6f (249 mg,
þ
7.20e7.40 (m, 4H); m/z (LCMS, ESI): found 310.3 [MþH]
;
1.0 mmol) were dissolved in 10 mL anhydrous DCE. After 10 min
NaBH (OAc)3 (318 mg, 1.5 mmol) and gl. AcOH (60 mg, 1.0 mmol)
were added to the mixture and left for stirring for 5 h at room
temperature. The crude product was obtained as colorless oil
[C16H24ClN3O
þ
H]þ requires 310.1; 300 MHz, 13C NMR
(CD3OD):175.7, 141.4, 134.3, 130.0, 127.2, 126.8, 125.8, 68.0, 57.3,
56.4, 52.0, 42.0, 31.0,30.2, 24.3, 9.1.
(275 mg, 59%). 500 MHz, 1H NMR (CDCl3-d1):
d 0.90e1.15 (m, 4H)
4.1.8.4. (S)-1-((R)-2-amino-3-phenylpropyl)-N-(3-chlorobenzyl)pyr-
rolidine-2-carboxamide hydrochloride (9f). Following the general
procedure for the reductive amination, compound 1 (50 mg,
1.20e1.32 (s, 9H) 1.50e1.80 (m, 3H) 1.91 (s, 1H) 2.00e2.12 (m, 1H)
2.40e2.53 (m, 2H) 2.60e2.70 (m, 2H) 3.13 (s, 2H) 3.91 (s, 1H)
4.24e4.51 (m, 3H) 7.00 (s, 2H) 7.14e7.25 (m, 4H) 7.50e7.51 (m, 2H)
8.00 (t, J ¼ 6.0 Hz, 1H) 8.50 (s, 1H); m/z (LCMS, ESI): found 463.2
[MþH] þ; [C27H34N4O3 þ H]þ requires 463.2.
0.21 mmol) TEA (30 mL, 0.21 mmol) and 6f (52 mg, 0.21 mmol) were
dissolved in 10 mL DCE. After 2 h, NaBH (OAc)3 (68 mg, 0.32 mmol)
was added to the mixture and left for stirring for 5 h at room
temperature. The product 8f was dissolved in 3 N methanolic HCl
(3 mL) and stirred for 3 h. The crude product was further purified by
reverse phase HPLC to give the final product as white solid (37 mg,
4.1.9. General procedure for the benzamidine synthesis
The cyano containing compound (1.0 eq) and Hydroxylamine
hydrochloride (5.0 eq) were dissolved in 20 mL anhydrous meth-
anol and left for 30 min stirring then DIEA (5.0 eq) was added. The
mixture was left stirring overnight and monitored by TLC. The re-
action solvent was removed under vacuum and the residue was
taken up in 50 mL EtOAc. The EtOAc was washed three times with
50 mL water followed by three times with 50 mL brine. The organic
layer was dried over anhydrous sodium sulfate, filtered and
concentrated to give the oxime. All the oximes were identified by
LCMS. The oxime (1.0 eq) was dissolved in 15 mL glacial acetic acid.
Acetic anhydride (1.2 eq) was added to the mixture and left to stir
for 30 min then 10% Pd/C (0.05 eq) was added and the mixture was
poured into the Parr bottle, which was put on to a Parr hydroge-
nation apparatus and the bottle was subjected to 3 charge/purge
cycles with hydrogen gas. The reaction was then charged with
50e55 psi hydrogen and shaken for 12 h. The reaction solvent was
filtered through celite to remove the Pd/C followed by several
acetonitrile washes of the bottle and celite. The Acetonitrile frac-
tions were combined and concentrated. If we have Boc-we proceed
further to dissolve the crude in 3 N methanolic HCl and left to stir
for 3 h then the solvent was evaporated under vacuum to give the
desired product. The crude products were further purified by RP-
50%). 500 MHz, 1H NMR (CD3OD):
d 1.80e1.90 (m, 3H) 2.20e2.35
(m, 2H) 2.72e2.85 (m, 2H) 2.90 (m, 1H) 3.05e3.15 (m, 1H) 3.33 (m,
2H) 3.55e3.60 (m, 1H) 4.35 (d, J ¼ 15 Hz, 1H) 4.55 (d, J ¼ 15 Hz, 1H)
þ
7.24e7.45 (m, 9H); m/z (LCMS, ESI): found 372.3 [MþH]
;
[C21H26ClN3O þ H]þ requires 372.1; High Resolution MS (ESI, m/z)
molecular ion was found 372.1841; 300 MHz, 13C NMR
(CD3OD):175.4, 141.2, 135.6, 133.9, 129.7, 128.9, 128.6, 127.2, 126.8,
125.5, 67.7, 56.7, 52.9, 51.9, 41.9, 36.7, 30.1, 23.5.
4.1.8.5. (S)-1-butyl-N-(4-cyanobenzyl)pyrrolidine-2-carboxamide
(14b). Following the general procedure for the reductive amina-
tion, compound 2 (250 mg, 1.09 mmol) TEA (150 mL, 1.09 mmol) and
butyraldehyde (79 mg, 1.09 mmol) were dissolved in 10 mL DCE.
After 2 h, NaBH (OAc)3 (346 mg, 1.63 mmol) was added to the
mixture and left for stirring for 5 h at room temperature. The crude
product was obtained as yellow oil (248 mg, 79%). 500 MHz, 1H
NMR (CDCl3-d1):
d 0.87e0.91 (m, 1H) 1.10e1.51 (m, 8H) 1.60e2.41
(m, 4H) 3.05e3.40 (m, 2H) 3.99e4.51 (m, 3H) 7.14 (s, 2H) 7.50 (s,
2H); m/z (LCMS, ESI): found 286.2 [MþH] þ; [C17H23N3O þ H]þ
requires 286.2.