Journal of Medicinal Chemistry
Article
which was capped and cooled in dry ice−acetone for 5 min. Pd/C (20
mg, 20% w/w) was added and mixed, and the flask was connected to a
PARR hydrogenator and shaken for 6 h at 35 PSI of H2. Upon
completion, the mixture was filtered through Celite. The solvent was
removed by distillation in vacuo and the residue partitioned between
water and DCM. The phases were separated, and the DCM was
concentrated in vacuo. The resulting residue was purified by column
chromatography on silica gel (50% EtOAc−hexanes), which upon
distillation of the solvents in vacuo afforded a yellowish-white solid (99
was pure by NMR. The product was further purified by recrystallizing
from ether−DCM to produce white crystals; mp 87−88 °C. 1H NMR
(400 MHz, CDCl3) δ 9.13 (s, 1H), 8.86 (s, 1H), 8.33 (s, 1H), 4.53 (d,
2H, J = 6 Hz), 4.42 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz). 13C
NMR (101 MHz, CDCl3) δ164.5, 155.3, 149.4, 140.0, 126.0, 120.0,
92.5, 81.0, 61.8, 51.2, 14.2. Anal. (C11H11NO3) C, H, N. HRMS calcd
for C11H11NO3: 228.0637 (M + Na). Found m/z: 228.0634 (M + Na).
5-(3-Hydroxypropyl)nicotinic Acid Ethyl Ester (14). Com-
pound 13 (270 mg, 1.32 mmol) was dissolved in methanol (8 mL)
and transferred to a Pyrex hydrogenation flask and cooled in dry ice−
acetone for 5 min. Pd/C (54 mg, 20% w/w) was added, and the flask
was attached to a PARR hydrogenator and shaken for 10 h at 30 PSI of
H2. Upon completion, the mixture was filtered through Celite and
solvents were removed in vacuo. The resulting residue was partitioned
between water and chloroform. The chloroform was concentrated
under reduced pressure and was purified by column chromatography
on silica gel (5% methanol−DCM), affording a yellow oil (245 mg,
1
mg, 93%). TLC Rf 0.31 (50% EtOAc−hexanes); mp 59−60 °C. H
NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.61 (s, 1H), 8.13 (s, 1H),
5.07 (s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 3.21 (q, 2H, J = 6.4 Hz), 2.73 (t,
2H, J = 8 Hz), 1.87 (m, 2H), 1.45 (s, 9H), 1.42 (t, 3H, J = 7.2 Hz). 13C
NMR (101 MHz, CDCl3) δ 165.4, 156.0, 153.4, 148.5, 136.8, 136.6,
126.0, 79.2, 61.4, 40.0, 31.4, 30.0, 28.4, 14.3. HRMS calcd for
C16H24N2O4: 331.1634 (M + Na). Found m/z: 331.1646 (M + Na).
5-(3-Aminopropyl)nicotinic Acid Ethyl Ester (10). Compound
9 (97.5 mg, 0.316 mmol) was dissolved in water (1 mL) and TFA (1
mL) and stirred for 2 h at 37 °C. The solvent was removed in vacuo,
forming a yellow colored oil. TLC Rf 0.67 in butanol−acetic acid−
1
89%). TLC Rf 0.37 in 5% methanol−DCM. H NMR (400 MHz,
CDCl3) δ 9.03 (s, 1H), 8.61 (s, 1H), 8.17 (s, 1H), 4.41 (q, 2H, J = 7.2
Hz), 3.71 (t, 2H, J = 6.4 Hz), 3.62 (s, 1H), 2.83 (t, 2H, J = 7.6 Hz),
1.93 (m, 2H), 1.42 (t, 3H, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3)
δ 165.4, 153.3, 148.2, 137.4, 137.0, 126.1, 61.5, 61.1, 33.7, 29.0, 14.4.
HRMS calcd for C11H15NO3: 232.0950 (M + Na). Found m/z:
232.0946 (M + Na).
1
water (5:2:3); Rf 0.12 in DCM−methanol−acetic acid (90:9:1). H
NMR (400 MHz, CD3OD) δ 9.17 (s, 1H), 8.90 (s, 1H), 8.77 (s, 1H),
4.47 (q, 2H, J = 7.2), 3.05 (t, 2H, J = 7.2 Hz), 2.99 (t, 2H, J = 8 Hz),
2.08 (m, 2H), 1.42 (t, 3H, J = 7.2 Hz). 13C NMR (101 MHz, CD3OD)
δ 164.3, 148.5, 144.7, 144.4, 141.7, 130.5, 63.7, 40.0, 30.3, 29.5, 14.6.
The compound was immediately taken to the next step in the
formation of 12.
5-(3-Hydroxypropyl)nicotinic Acid (15). Compound 14 (156
mg, 0.746 mmol) was dissolved in methanol (2 mL) and 4 N NaOH
(1 mL) and stirred at 37 °C for 4 h. After this time, the solvent was
evaporated in vacuo, the residue dissolved in water, and the alkali
neutralized using 1 N HCl. After the water was removed by
lyophilization, the residue was applied to a Combiflash C18 cartridge
(15.5 g) and eluted isocratically with water. The mixture was
concentrated in vacuo and applied to a 35 mL (bed volume) column
of Amberchrom resin (CG71M, Dow Chemical Company, product no.
10235577; Copenhagen, Denmark), which sufficiently desalted the
mixture (isocratic, water). Upon drying, a yellowish-white solid was
obtained (129 mg, 96%); mp 216−218 °C. TLC Rf 0.16 in DCM−
methanol−acetic acid (90:9:1). TLC Rf 0.69 in butanol−acetic acid−
5-[3-[(tert-Butyloxy)carbonyl]aminopropyl]nicotinic Acid
(11). Compound 9 (100 mg, 0.324 mmol) was dissolved in methanol
(2 mL) and 4 N NaOH (1 mL) and stirred at 37 °C for 4 h. After this
time, the solvent was removed and the product was dried in vacuo
then neutralized by dissolving in 1 N HCl. The water was removed by
lyophilization, then the product was immediately purified by column
chromatography on silica gel (90:9:1 DCM−methanol−acetic acid),
affording a yellowish-white solid (81 mg, 89%); mp 225−227 °C. TLC
Rf 0.47 in DCM−methanol−acetic acid (90:9:1); Rf 0.79 in butanol−
1
acetic acid−water (5:2:3). H NMR (400 MHz, CD3OD) δ 8.89 (s,
1
1H), 8.41 (s, 1H), 8.17 (s, 1H), 3.10 (t, 2H, J = 6.4 Hz), 2.71 (t, 2H, J
= 8 Hz), 1.82 (m, 2H), 1.43 (s, 9H). 13C NMR (150 MHz, CD3OD) δ
172.8, 158.6, 151.1, 148.9, 138.8, 138.7, 134.9, 80.0, 40.9, 32.5, 31.0,
28.9. Anal. (C14H20N2O4·0.5DCM) C, H, N.
water (5:2:3). H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.42 (s,
1H), 8.19 (s, 1H), 3.59 (t, 2H, J = 6.4 Hz), 2.77 (t, 2H, J = 8 Hz), 1.87
(m, 2H). 13C NMR (150 MHz, CD3OD) δ 173.0, 151.2, 148.9, 139.0,
138.7, 135.0, 61.9, 35.0, 30.1. HRMS calcd for C9H11NO3: 182.0817
(M + H). Found m/z: 182.0821 (M + H).
5-(3-Aminopropyl)nicotinic Acid (12). Compound 9 (100 mg,
0.324 mmol) was dissolved in water (2 mL) and TFA (1 mL) and was
stirred at rt for 8 h. The solvents were evaporated in vacuo. The crude
residue was examined, and NMR verified the removal of the t-Boc
group, while the ethyl ester was intact. The sample was then dissolved
in methanol (4 mL) and 4 N NaOH (2 mL) and the mixture allowed
to stir at rt for 8 h. The reaction mixture was neutralized with 1 N
HCl, and solvents were removed in vacuo. The relatively pure mixture
which resulted was further purified by reverse phase chromatography
on a C18 cartridge (15.5 g, 13.5 mL void volume) using a Combiflash
Rf system. The product eluted between column volumes 3 and 4 in an
isocratic (water) system. Removal of water by lyophilization yielded a
white solid (48 mg, 83%); mp 270−272 °C. TLC Rf 0.33 in butanol−
acetic acid−water (5:2:3). 1H NMR (600 MHz, D2O) δ 8.59 (s, 1H),
8.23 (s, 1H), 7.87 (s, 1H), 2.9 (t, 2H, J = 6.4 Hz), 2.59 (t, 2H, J = 8
Hz), 1.85 (m, 2H). 13C NMR (150 MHz, D2O) δ 172.9, 150.2, 147.0,
137.2, 136.3, 132.0, 38.9, 28.8, 28.0. HRMS calcd for C9H12N2O2:
181.0977 (M + H). Found m/z: 181.0981 (M + H).
5-(3-Hydroxy-1-propynyl)nicotinic Acid Ethyl Ester (13). To a
solution of 2e (250 mg, 1.09 mmol), Pd(PPh3)2Cl2 (38 mg, 0.0545
mmol), and DIPEA (423 mg, 3.27 mmol) in acetonitrile (5 mL) was
added propargyl alcohol (73 mg, 1.31 mmol) and CuI (15 mg, 0.0763
mmol) while stirring under N2. After the addition was complete, the
reaction mixture was refluxed for 16 h. At this time, TLC indicated
that the starting material was consumed. Solvents were removed in
vacuo and the residue partitioned between water and chloroform. The
phases were separated, and chloroform was concentrated in vacuo.
The resulting oil was purified by column chromatography on silica gel
(50% EtOAc−hexanes), affording a yellow solid (160 mg, 71%) that
5-[3-(p-Methylbenzenesulfonyl)propyl]nicotinic Acid Ethyl
Ester (16). Compound 14 (107 mg, 0.51 mmol) was dissolved in dry
DCM (5 mL). To this solution was added p-methylbenzenesulfonyl
chloride (292 mg, 1.5 mmol) and TEA (114 mg, 1.12 mmol). The
mixture was refluxed for 16 h. Upon TLC analysis in 50% EtOAc−
hexanes, starting material was still present. Additional p-toluenesul-
fonyl chloride (50 mg, 0.26 mmol) and TEA (15 mg, 0.15 mmol) were
added to the mixture and allowed to stir at reflux for an additional 12
h. This pushed the reaction to completion, and the product was
isolated by removal of solvents by distillation and the residue
partitioned between saturated sodium bicarbonate (50 mL) and DCM
(50 mL). The organic layer was further washed with brine (3×). The
phases were separated, and the DCM was evaporated in vacuo. The
crude material was purified by chromatography on silica gel in 50%
EtOAc−hexanes to obtain a colorless oil (94 mg, 51%). TLC Rf 0.27
1
50% EtOAc−hexanes. H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H),
8.54 (s, 1H). 8.07 (s, 1H), 7.79 (d, 2H), 7.35 (d, 2H), 4.41 (q, 2H, J =
7.2 Hz), 4.06 (t, 2H, J = 6 Hz), 2.75 (t, 2H, J = 8 Hz), 2.46 (s, 3H),
2.00 (m, 2H), 1.42 (t, 3H, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3)
δ165.4, 153.6, 149.0, 145.2, 136.8, 135.8, 133.0, 130.11, 129.92, 128.0,
126.3, 125.3, 69.2, 61.7, 30.2, 28.7, 21.8, 14.4.
5-(3-Azidopropyl)nicotinic Acid Ethyl Ester (17). To a solution
of 16 (47 mg, 0.13 mmol) in dry DMF (2 mL) was added sodium
azide (17 mg, 0.26 mmol). The reaction mixture was stirred and
heated for 18 h at 60 °C. Upon completion, solvents were distilled
under reduced pressure and the residue purified by column
chromatography on silica gel in 50% EtOAc−hexanes, yielding a
yellow oil (22 mg, 73%). TLC Rf 0.49 in 50% EtOAc−hexanes; Rf 0.77
3604
J. Med. Chem. 2015, 58, 3593−3610