MedChemComm
Research Article
pyridine-3-carboxamide (32). Carboxylic acid 31 (70 mg, 0.16
mmol) was dissolved in anhydrous DMF (2.5 mL) and
meldrum's acid derivative 35 (19.6 g, 62.7 mmol) were
dissolved in DCM (73 ml) and TFA (1.61 ml, 20.9 mmol) was
added. The solution was split into 7 vials which were then
capped and heated to 70 °C for 20 h. Quenched with NaHCO3
(sat. aq). The water layer was extracted with EtOAc and the
3
0
-fluoro-5-methylaniline (36 μL, 0.32 mmol), HATU (74 mg,
.19 mmol) and diisopropyl ethyl amine (57 μL, 0.33 mmol)
were added and stirred at rt for 4 h. The reaction mixture
was cooled on ice and quenched by addition of 0.5 M HCl(aq)
2 4
organic layers were dried (Na SO ), filtered and concentrated.
(4 mL) in portions, diluted with EtOAc and the aqueous layer
Purified using column chromatography on silica gel
was extracted with EtOAc (×2). The combined organic layers
were washed successively with 0.5 M HCl(aq) and brine, dried
(heptane : EtOAc 60 : 40 ≥ 0 : 100) to give methyl ester 36 as a
1
yellow foam (8.12 g, 85%). H-NMR (400 MHz, CDCl
3
) δ 7.90–
(
Na SO ) and concentrated under reduced pressure.
7.73 (m, 3H), 7.52–7.41 (m, 2H), 7.41–7.28 (m, 6H), 7.24–7.18
(m, 1H), 5.93 (s, 1H), 5.80–5.65 (m, 1H), 5.54 (dd, J = 8.4, 2.4
Hz, 1H), 5.20–5.10 (m, 2H), 4.27–4.05 (m, 2H), 3.76 (s, 3H),
2
4
Purification by flash chromatography (SiO , 40–100% EtOAc
in heptane) and freeze-drying from
2
2
H O : MeCN (5 : 1)
1
3
afforded the amide 32 as an orange powder (43 mg, 49%).
3.73–3.63 (m, 1H), 3.55–3.45 (m, 1H); C-NMR (100 MHz,
1
H-NMR (600 MHz, DMSO-d ) δ 10.55 (s, 1H), 9.32 (s, 1H),
CDCl ) δ 168.3, 161.0, 154.9, 154.8, 148.4, 135.9, 134.1, 132.9,
6
3
7
7
7
5
1
2
.98–7.95 (m, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.88–7.85 (m, 1H),
.54–7.49 (m, 3H), 7.43 (d, J = 6.9 Hz, 1H), 7.30–7.26 (m, 1H),
.10 (s, 1H), 6.76–6.72 (m, 1H), 5.48 (dd, J = 9.3, 2.0 Hz, 1H),
.04 (s, 1H), 4.46, 4.32 (ABq, JAB = 17.7 Hz, 2H), 4.01 (dd, J =
1.9, 9.3 Hz, 1H), 3.59 (dd, J = 11.9, 2.0 Hz, 1H), 3.21 (s, 3H),
132.0, 128.9, 128.7, 128.5, 128.3, 128.1, 127.7, 126.5, 126.0,
125.6, 124.0, 115.5, 111.5, 67.8, 64.0, 53.5, 34.9, 32.2; HRMS
+
+ +
+
(ESI ) (m/z): [M + H ] calcd. for C H N O S , 501.1479;
28
25 2 5
found, 501.1476.
BenzylIJ7-(naphthalen-1-ylmethyl)-5-oxo-3-(3-phenyl-1H-
1,2,4-triazol-5-yl)-3,5-dihydro-2H-thiazoloij3,2-a]pyridin-8-yl)-
carbamate (37). Methyl ester 36 (300 mg, 0.600 mmol) was
dissolved in THF (2.2 ml) and 1 M LiOH(aq) (1.2 ml) was
added. Stirred at room temperature for 2 h. Diluted with
EtOAc and washed with 1 M HCl. The organic layer was dried
(Na SO ), filtered and concentrated. The residue was
1
3
6
.27 (s, 3H). C-NMR (151 MHz, DMSO-d ) δ 165.9, 162.0 (d,
JCF = 141.0 Hz), 159.4, 156.3, 151.6, 140.6 (d, JCF = 9.6 Hz),
1
1
1
4
39.8 (d, JCF = 12.1 Hz), 133.8, 133.5, 131.5, 128.6, 128.3,
27.6, 126.3, 125.9, 125.7, 124.2, 115.4 (CF broad peak), 112.7,
10.8 (d, JCF = 21.2 Hz), 109.9, 103.2 (d, JCF = 26.4 Hz), 65.0,
3.3, 34.4, 21.0 (d, JCF = 2.0 Hz). HRMS (ESI ) (m/z): [M + H ]
, 538.1265; found, 538.1273.
-(Methylsulfonamido)-7-(naphthalen-1-ylmethyl)-5-oxo-N-
+
+ +
2
4
calcd. for C27
H25FN O S
3 4 2
dissolved in dry DMF (3.6 ml) and benzamidine
hydrochloride hydrate (154 mg, 0.88 mmol), DIPEA (305 μl,
1.76 mmol) and HATU (257 mg, 0.676 mmol) were added.
Stirred at room temperature for 3.5 h (4-methoxybenzyl)-
hydrazine hydrochloride (166 mg, 0.882 mmol) and AcOH
(337 μl, 5.88 mmol) were added and the mixture was heated
to 80 °C for 20 h. Cooled to room temperature and quenched
8
(
(
m-tolyl)-2,3-dihydrothiazoloij3,2-a]pyridine-3-carboxamide
33). Carboxylic acid 31 (70 mg, 0.16 mmol) was dissolved in
anhydrous DMF (2.5 mL) and 3-methylaniline (34 μL, 0.32
mmol), HATU (74 mg, 0.19 mmol), and diisopropyl ethyl
amine (57 μL, 0.33 mmol) were added and stirred under an
inert atmosphere at rt for 4 h. The reaction mixture was
cooled on ice and quenched by addition of 0.5 M HCl(aq) (4
mL) in portions, diluted with EtOAC and aqueous layer was
extracted with EtOAc (×2). The combined organic layers were
washed successively with 0.5 M HCl(aq) and brine (2 mL 0.5
with NaHCO
were washed with NaHCO3 (sat. aq), 5% LiCl, water, and
brine and then dried (Na SO ), filtered, and concentrated.
3
(aq). Extracted with EtOAc. The organic layers
2
4
The residue was suspended in DCM (3.6 ml) and TFA (3.6
ml) was added. Heated to 50 °C for 22 h. Concentrated,
M HCl(aq) was added to aid separation), dried (Na
2 4
SO ) and
3
dissolved in EtOAc and washed with NaHCO (sat. aq). The
concentrated under reduced pressure. Purification by flash
water layer was extracted with EtOAc and the organic layers
were then washed with water and brine. Dried (Na SO ),
chromatography (SiO , EtOAc in heptane, 70–100%) and
2
2
4
freeze-drying from H
as beige powder (66 mg, 78%). H-NMR (600 MHz, DMSO-d
δ 10.32 (s, 1H), 9.32 (s, 1H), 7.99–7.95 (m, 1H), 7.92–7.85 (m,
2
O : MeCN (5 : 1) afforded the amide 33
filtered and concentrated. Purified using column
1
6
)
chromatography on silica gel (heptane : EtOAc 25 : 75 ≥ 0 :
100) followed by preperative HPLC (H O : MeCN 90 : 10 ≥ 0 :
2
2
7
5
=
1
H), 7.55–7.49 (m, 3H), 7.44–7.42 (m, 1H), 7.41–7.39 (m, 1H),
.31–7.27 (m, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.90–6.86 (m, 1H),
.49 (dd, J = 9.2, 2.0 Hz, 1H), 5.04 (s, 1H), 4.46, 4.32 (ABq, JAB
17.7 Hz, 2H), 4.01 (dd, J = 11.8, 9.2 Hz, 1H), 3.58 (dd, J =
100 with 0.75% formic acid over 40 minutes) to give 1,2,4-
1
triazole 37 as a yellow solid (135 mg, 39%). H-NMR (400
MHz, CDCl ) δ 7.87–7.85 (m, 4H), 7.72 (d, J = 8.4 Hz, 1H),
3
7.46–7.36 (m, 2H), 7.35–7.21 (m, 9H), 7.11 (d, J = 7.1 Hz, 1H),
6.48 (s, 1H), 6.20 (d, J = 7.3 Hz, 1H), 5.68 (s, 1H), 5.13 (s, 2H),
1
3
1.8, 2.0 Hz, 1H), 3.21 (s, 3H), 2.25 (s, 3H). C-NMR (151
13
MHz, DMSO-d ) δ 165.6, 159.5, 156.2, 151.6, 138.5, 138.1,
4.17, 3.95 (ABq, JAB = 17.6 Hz, 2H), 3.78–3.66 (m, 2H); C-
NMR (100 MHz, CDCl ) δ 161.7, 158.3, 157.6, 155.7, 155.1,
6
1
1
3
33.9, 133.5, 131.5, 128.7, 128.6, 128.3, 127.6, 126.3, 125.9,
25.7, 124.33, 124.25, 119.6, 116.2, 112.7, 109.9, 65.0, 43.3,
4.4, 32.1, 21.1. HRMS (ESI ) (m/z): [M + H ] calcd. for
3
157.7, 136.0, 134.0, 132.9, 131.9, 130.0, 128.8, 128.8, 128.7,
128.7, 128.4, 128.2, 128.0, 127.8, 126.6, 126.5, 125.9, 125.6,
124.1, 115.0, 112.4, 67.7, 60.8, 34.7, 33.7; LRMS (m/z): [M +
+
+ +
27 26 3 4 2
C H N O S , 520.1359; found, 520.1362.
+
+
+
Methyl
8-(((benzyloxy)carbonyl)amino)-7-(naphthalen-1-
28 5 3
H ] calcd. for C34H N O S, 586.2 ; found, 586.3.
ylmethyl)-5-oxo-3,5-dihydro-2H-thiazoloij3,2-a]pyridine-3-
carboxylate (36). Thiazoline 34 (5.86 g, 19.0 mmol) and acyl
N-(7-(Naphthalen-1-ylmethyl)-5-oxo-3-(3-phenyl-1H-1,2,4-
triazol-5-yl)-3,5-dihydro-2H-thiazoloij3,2-a]pyridin-8-yl)-
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Med. Chem. Commun., 2019, 10, 1966–1987 | 1983