ACCEPTED MANUSCRIPT
Diethyl 2-(1-(5,6-Dimethoxybenzo[b]thiophen-2-yl)-1-oxopropan-2-yl)malonate (10).
To a suspension of anhydrous potassium carbonate (1.36 g, 9.8 mmol) in dry DMF (60
mL) at room temperature, diethyl malonate (2.58 g, 16 mmol) was added. After the
reaction mixture stirred for 3 h at room temperature, bromoketone 9 (5.0 g, 15.2 mmol)
was added and the reaction was heated at 110 °C overnight. After cooling, the reaction
was quenched into water (250 mL) and extracted with ethyl acetate (3 x 50 mL). The
combined organic layer was washed with water, dried over sodium sulfate and
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concentrated under reduced pressure to afford 10 as a brown oily compound. H NMR
(
400 MHz, acetone-d ) δ 8.25 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H),
6
4
6
1
1
.18 – 4.02 (m, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (d, J = 10.8 Hz, 1H), 1.35 – 1.27 (m,
1
3
H), 1.15 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, acetone-d ) δ 195.6, 169.0, 168.6,
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52.6, 150.3, 140.8, 137.7, 133.9, 131.1, 107.5, 104.8, 62.2, 62.0, 56.4, 56.2, 55.7, 42.3,
+
7.0, 14.4, 14.2. HRMS calcd for C20
H
24
O
7
S (M+Na) 431.1135, found 431.1144.
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-(5,6-Dimethoxybenzo[b]thiophen-2-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one
(ORG9935). The crude diethyl malonate 10 (2.28 g, 5.58 mmol), was dissolved in
methanol (50 mL) and water (10 mL) and sodium hydroxide (0.720 g, 18 mmol) was
added. After the reaction was refluxed overnight the methanol was removed under
reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 50 mL),
washed with brine and dried over sodium sulfate. The ethyl acetate was distilled off
under reduced pressure, ethanol was (60 mL) was added and then hydrazine hydrate
(85%, 6.25 mL). The reaction was heated at reflux overnight, cooled to 40 °C and
filtered. The solid was washed with plenty of water and dried at 40 °C under reduced
pressure to afford pure ORG9935 (0.935 g) as a cream colored solid in 55% yield over
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three steps. MP 223 – 225 °C. H NMR (400 MHz, DMSO-d ) δ 10.96 (s, 1H), 7.64 (s,
6
1
=
H), 7.49 (s, 1H), 7.33 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.45 – 3.38 (m, 1H), 2.76 (dd, J
1
3
16.8, 6.9 Hz, 1H), 2.27 (d, J = 16.7 Hz, 1H), 1.14 (d, J = 7.4 Hz, 3H). C NMR (100
) δ 166.2, 149.8, 149.1, 147.9, 137.9, 132.8, 132.8, 124.0, 105.7, 104.4,
MHz, DMSO-d
5
3
6
+
5.7, 55.5, 33.4, 28.0, 16.4. HRMS calcd for C15
27.0774.
16 2 3
H N O S (M+Na) 327.0774, found
Ethyl 4-(5,6-Dimethoxybenzo[b]thiophen-2-yl)-3-methyl-4-oxobutanoate (11). To a
stirred solution of intermediate 8 (30 g, 120 mmol) in anhydrous THF (200 mL) and
HMPA (75 mL) was added LiHMDS in THF (1.0 mol/L, 132 mL) at –70 °C under an
inert atmosphere. After stirring for 20 min at the same temperature, ethyl bromoacetate
(25.5 g, 152.7 mmol) was added dropwise to the reaction mixture at –70 °C, and then the
reaction mixture was stirred overnight at room temperature. After the reaction mixture
was cooled to –20 °C, saturated NH Cl solution (50 mL) was added slowly and then
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water (300 mL). After extraction with ethyl acetate (3 x 350 mL), the combined organic
layer was washed with brine, dried over Na SO , and concentrated under reduced
2
4
pressure. The target compound 11 was obtained as cream colored solid and used in the
next step without further purification.
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-(5,6-Dimethoxybenzo[b]thiophen-2-yl)-3-methyl-4-oxobutanoic Acid (5). To a
stirred solution of intermediate 11 (40 g, crude) in ethanol (250 mL) and water (100 mL)
was added a NaOH solution (6.18 g, 154 mmol / 50 mL water) dropwise at room
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