Reaction #45498

Reaction equation

sodium borohydride

N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide

4-formylimidazole

sodium hydroxide

→

title compound

N-[4-(4-amino-7-{(1E)-3-[(1H-benzimidazol-4-ylmethyl)amino]prop-1-enyl}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide

Solvents

methanol

methylene chloride

toluene

Conditions

Workup

1. 1
   OtherIn a round bottom flask was combined
2. 2
   OtherThe flask was flushed with nitrogen gas
3. 3
   TemperatureThe reaction mixture was cooled to room temperature
4. 4
   FiltrationThe mixture was filtered through an Empore™ cartridge
5. 5
   Otherthe solvents removed
6. 6
   Otherthe product purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm
7. 7
   workup.WAIT5% acetonitrile—0.1M ammonium acetate isocratic for 5 minutes
8. 8
   workup.WAIT5-100% acetonitrile—0.1M ammonium acetate over 30 min
9. 9
   OtherThe acetonitrile was removed

Procedure

In a round bottom flask was combined N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol), 4-formylimidazole (0.0083 g, 0.086 mmol), and toluene (1.5 mL). The flask was flushed with nitrogen gas, followed by the addition of titanium (IV) isopropoxide (0.061 g, 0.215 mmol). The mixture was heated under a nitrogen atmosphere to 50° C. for 16 hours. The reaction mixture was cooled to room temperature and treated with methanol (1 mL) and sodium borohydride (0.010 g, 0.263 mmol). The resulting mixture was stirred for 12 hours at room temperature, followed by the addition of a 10% aqueous solution of sodium hydroxide (5 mL) and methylene chloride (5 mL). The mixture was filtered through an Empore™ cartridge, the solvents removed, and the product purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 5% acetonitrile—0.1M ammonium acetate isocratic for 5 minutes, then 5-100% acetonitrile—0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed and the aqueous solution was lyophilized to give the title compound as an off-white solid: 0.012 g (24%): LCMS (Conditions b): MH+=467.3, RT=2.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1 H), 7.99 (d, J=8.2 Hz, 1 H), 7.95 (s, 1 H), 7.70 (d, J=8.2 Hz, 1 H), 7.62 (s, 1 H), 7.59 (d, J=8.6 Hz, 1 H), 7.55 (s, 1 H), 7.35 (s, 1 H), 7.32 (d, J=8.6 Hz, 1 H), 7.21 (d, J=1.6 Hz, 1 H), 7.15 (dd, J=7.8 Hz, 7.0 Hz, 1 H), 7.08 (dd, J=7.8 Hz, 1.6 Hz, 1 H), 6.88 (s (br), 1 H), 6.67 (d, J=16.0 Hz, 1 H), 6.30 (td, J=16.4 Hz, 5.5 Hz, 1 H), 5.61 (s (br), 1 H), 4.04 (s, 3 H), 3.91 (s, 3 H), 3.67 (s, 2 H), 3.39 (d, J=5.5 Hz, 2 H), 2.78 (s, 15 H, acetate)

Source