Journal of Medicinal Chemistry
Article
amino-quinazoline-8-carboxylic acid [2,6-difluoro-3-(propane-1-sulfo-
nylamino)-phenyl]-amide 24. HPLC RT = 9.07 min (method B). ESI-
MS: m/z 438.0 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 13.47 (s,
1H), 9.90 (s, 1H), 8.65 (dd, J = 7.5, 1.4 Hz, 1H), 8.58 (s, 1H), 8.53
(dd, J = 8.3, 1.4 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 7.9
Hz, 1H), 7.47−7.36 (m, 2H), 3.16−3.08 (m, 2H), 1.75 (sx, J = 7.4 Hz,
2H), 0.97 (t, J = 7.4 Hz, 3H).
d]pyrimidine-7-carboxylate (2.00 g, 8.75 mmol) in THF (60 mL) and
water (20 mL) was added lithium hydroxide monohydrate (0.59 g,
14.0 mmol). The reaction mixture was stirred at room temperature for
2 h, after which the volatiles were concentrated in vacuo. Water was
added and a solid was obtain after filtration, which was rinsed with
water and dried on a lyophilizer to afford 4-chlorothieno[3,2-
1
d]pyrimidine-7-carboxylic acid (1.56 g, 81%). H NMR (500 MHz,
4-Amino-quinazoline-8-carboxylic Acid [2-Chloro-6-fluoro-
3-(propane-1-sulfonylamino)-phenyl]-amide (26). Step A: 4-
Chloro-N-(2-chloro-6-fluoro-3-(propylsulfonamido)phenyl)-
quinazoline-8-carboxamide 23c was made using a similar procedure as
described for 4-chloro-N-(2,6-difluoro-3-(propylsulfonamido)phenyl)-
quinazoline-8-carboxamide 23a. Step B: 4-Amino-quinazoline-8-
carboxylic acid [2-chloro-6-fluoro-3-(propane-1-sulfonylamino)-phe-
nyl]-amide 26 was made using a similar procedure as described for 4-
amino-quinazoline-8-carboxylic acid [2,6-difluoro-3-(propane-1-sulfo-
nylamino)-phenyl]-amide 24. HPLC RT = 8.00 min (method B). ESI-
MS: m/z 438.0 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s,
1H), 9.68 (s, 1H), 8.69−8.61 (m, 1H), 8.57 (s, 1H), 8.56−8.49 (m,
1H), 8.32 (s, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.37 (td, J = 8.8, 5.7 Hz,
1H), 7.22 (t, J = 8.7 Hz, 1H), 3.15−3.03 (m, 2H), 1.84−1.68 (m, 2H),
1.04 (d, J = 6.1 Hz, 1H), 1.02−0.93 (m, 3H).
4-Amino-quinazoline-8-carboxylic Acid [6-Chloro-2-fluoro-
3-(3-fluoro-propane-1-sulfonylamino)-phenyl]-amide (27).
S t e p A : 4 - C h l o r o - N - ( 6 - c h l o r o - 2 - f l u o r o - 3 - ( 3 -
fluoropropylsulfonamido)phenyl)quinazoline-8-carboxamide 23d was
made using a similar procedure as described for 4-chloro-N-(2,6-
difluoro-3-(propylsulfonamido)phenyl)quinazoline-8-carboxamide
23a. Step B: 4-Amino-quinazoline-8-carboxylic acid [6-chloro-2-fluoro-
3-(3-fluoro-propane-1-sulfonylamino)-phenyl]-amide 27 was made
using a similar procedure as described for 4-amino-quinazoline-8-
carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-
amide 24. HPLC RT = 3.40 min (method A). ESI-MS: m/z 456.1,
458.1 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 9.98
(s, 1H), 8.68−8.62 (m, 1H), 8.58 (s, 1H), 8.55−8.50 (m, 1H), 8.30
(br s, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.47−7.37 (m, 2H), 4.60 (t, J = 6.0
Hz, 1H), 4.48 (t, J = 6.0 Hz. 1H), 3.27−3.21 (m, 2H), 2.19−2.04 (m,
2H).
DMSO-d6) δ 8.98 (s, 1H), 8.69 (s, 1H).
4-Amino-thieno[3,2-d]pyrimidine-7-carboxylic Acid [6-
Chloro-2-fluoro-3-(propane-1-sulfonylamino)-phenyl]-amide
(33). Step A: To a solution of 4-chlorothieno[3,2-d]pyrimidine-7-
carboxylic acid 30 (0.93 g, 4.31 mmol) in THF (45 mL) at 0 °C was
added oxalyl chloride (730 μL, 8.63 mmol) followed by DMF (14.5
μL, 0.19 mmol). The reaction mixture was stirred at room temperature
for 75 min and then concentrated in vacuo to give crude 4-
chlorothieno[3,2-d]pyrimidine-7-carbonyl chloride, which was used
directly in the next step. Step B: Crude 4-chlorothieno[3,2-
d]pyrimidine-7-carbonyl chloride was dissolved in THF (40 mL),
and N-(3-amino-4-chloro-2-fluorophenyl)propane-1-sulfonamide 7b
(1.00 g, 3.75 mmol) was added. The reaction mixture was stirred at
55 °C for 90 min, cooled to room temperature, and diluted with
dichloromethane and a saturated aqueous solution of NaHCO3. The
layers were separated and the aqueous layer extracted with
dichloromethane (2×). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography to afford 4-chloro-N-(6-
chloro-2-fluoro-3-(propylsulfonamido)phenyl)thieno[3,2-d]-
1
pyrimidine-7-carboxamide 31b (1.65 g, 95%). H NMR (500 MHz,
DMSO-d6) δ 10.72 (s, 1H), 9.88 (s, 1H), 9.36 (s, 1H), 9.26 (s, 1H),
7.47−7.42 (m, 2H), 3.19−3.07 (m, 2H), 1.79−1.71 (m, 2H), 0.98 (t, J
= 7.4 Hz, 3H). ESI-MS: m/z 463.0, 465.0 (M + 1). Step C: A sealed
tube was charged with 4-chloro-N-(6-chloro-2-fluoro-3-
(propylsulfonamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
31b (1.65 g, 3.56 mmol), and a 2 M ammonia solution in isopropyl
alcohol (27 mL) was added. The reaction mixture was heated at 95 °C
for 24 h and then concentrated in vacuo. The crude product was
triturated with 2% i-PrOH/water solution (crude could also be
purified by reverse phase HPLC) to afford the title compound (1.41 g,
89%). HPLC RT = 9.69 min (method B). ESI-MS: m/z 444.0 (M +
Methyl 4-Hydroxythieno[3,2-d]pyrimidine-7-carboxylate
(29). Step A: To a solution of 3H-thieno[3,2-d]pyrimid-4-one 28
(25 g, 164 mmol) in acetic acid (200 mL) was added bromine (26
mL) dropwise. The reaction mixture was heated at 100 °C for 8 h. The
resulting suspension was cooled to room temperature, poured into
water, and neutralized with solid sodium bicarbonate. The solid
product was collected by vacuum filtration to yield 7-bromo-3H-
1
1). H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.90 (s, 1H),
8.98 (s, 1H), 8.55 (s, 1H), 7.97 (s, 2H), 7.49−7.36 (m, 2H), 3.18−
3.07 (m, 2H), 1.81−1.67 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).
4-Amino-thieno[3,2-d]pyrimidine-7-carboxylic Acid [2,6-Di-
fluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (32). Step
A: 4-Chloro-N-(2,6-difluoro-3-(propylsulfonamido)phenyl)thieno-
[3,2-d]pyrimidine-7-carboxamide 31a was made using a similar
procedure as described for 4-chloro-N-(6-chloro-2-fluoro-3-
(propylsulfonamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
31b. Step B: 4-Amino-thieno[3,2-d]pyrimidine-7-carboxylic acid [2,6-
difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide 32 was made
using a similar procedure as described for 4-amino-thieno[3,2-
d]pyrimidine-7-carboxylic acid [6-chloro-2-fluoro-3-(propane-1-sulfo-
nylamino)-phenyl]-amide 33. HPLC RT = 8.72 min (method B). ESI-
MS: m/z 428.0 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s,
1H), 9.62 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 7.97 (s, 2H), 7.47 (dd, J
= 9.1, 5.3 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H), 3.18−3.09 (m, 2H), 1.77
(dd, J = 15.2, 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).
1
thieno[3,2-d]pyrimid-4-one (21.4 g, 60%) as a solid. H NMR (500
MHz, DMSO-d6) δ 12.75 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H). Step B:
7-Bromo-3H-thieno[3,2-d]pyrimid-4-one (10.0 g, 40.7 mmol), [1,1′-
bis-(diphenyl-phosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (830.5 mg, 1.017 mmol), triethylamine
(28.35 mL, 203.4 mmol), and methanol (80 mL) were combined in an
autoclave fitted with a large stir bar. The mixture was purged with
nitrogen for 5 min. The vessel was placed under an atmosphere of
carbon monoxide (300 psi) and heated to 120 °C for 3 h. The vessel
was cooled to room temperature, and the reaction mixture was filtered.
The collected solids were washed with methanol (250 mL). The solids
were air-dried to give the title compound (6.8 g, 80%). 1H NMR (400
MHz, DMSO-d6) δ 12.74 (s, 1H), 8.90 (s, 1H), 8.27 (s, 1H), 3.89 (s,
3H).
4-Chlorothieno[3,2-d]pyrimidine-7-carboxylic Acid (30). Step
A: Methyl 4-hydroxythieno[3,2-d]pyrimidine-7-carboxylate 29 (6.8 g,
31 mmol) was dissolved in phosphoryl chloride (100 mL, 1000 mmol)
and heated to reflux for 2 h. The mixture was stirred at room
temperature overnight. The phosphoryl chloride was distilled off, and
the solids were neutralized with ice and sodium bicarbonate. The
resulting suspension was filtered to give a solid, which was triturated
with anhydrous ether. The resulting suspension was filtered to yield
methyl 4-chlorothieno[3,2-d]pyrimidine-7-carboxylate as a solid (6.76
g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.17 (s, 1H),
3.91 (s, 3H). Step B: To a solution of methyl 4-chlorothieno[3,2-
4-Amino-thieno[3,2-d]pyrimidine-7-carboxylic Acid [2-
Chloro-6-fluoro-3-(propane-1-sulfonylamino)-phenyl]-amide
(34). Step A: 4-Chloro-N-(2-chloro-6-fluoro-3-(propylsulfonamido)-
phenyl)thieno[3,2-d]pyrimidine-7-carboxamide 31c was made using a
similar procedure as described for 4-chloro-N-(6-chloro-2-fluoro-3-
(propylsulfonamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
31b. Step B: 4-Amino-thieno[3,2-d]pyrimidine-7-carboxylic acid [2-
chloro-6-fluoro-3-(propane-1-sulfonylamino)-phenyl]-amide 34 was
made using a similar procedure as described for 4-amino-thieno[3,2-
d]pyrimidine-7-carboxylic acid [6-chloro-2-fluoro-3-(propane-1-sulfo-
nylamino)-phenyl]-amide 33. HPLC RT = 9.06 min (method B). ESI-
MS: m/z 444.0 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s,
1H), 9.62 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 7.97 (s, 2H), 7.47 (dd, J
2879
dx.doi.org/10.1021/jm300016v | J. Med. Chem. 2012, 55, 2869−2881