Sodium Hydroxide → 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

HRID 2390720Notes

Reaction equation

HRID 2390720 reaction equation
[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH:36]([C:38]1[N:39]=[CH:40][NH:41][CH:42]=1)=O.[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl.CO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:1][CH2:2][C:7]2[C:42]3[N:41]=[CH:40][NH:39][C:38]=3[CH:36]=[CH:5][CH:6]=2)=[CH:4][N:3]=1

Participants

9

Reactant 4

HCID 14798Sodium HydroxideHCID 764281H-Imidazole-4-carbaldehydeHCID 4311764Sodium borohydrideHCID 18451050N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide

Product 1

HCID 68678346n-[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

Reagents, catalysts & solvents 4

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

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, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15 (dd, J=7.8 Hz, 7.0 Hz, 1H), 7.08 (dd, J=7.8 Hz, 1.6 Hz, 1H), 6.88 (s (br), 1H), 6.67 (d, J=16.0 Hz, 1H), 6.30 (td, J=16.4 Hz, 5.5 Hz, 1H), 5.61 (s (br), 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.67 (s, 2H), 3.39 (d, J=5.5 Hz, 2H), 2.78 (s, 15H, acetate)

Workup

  1. customIn a round bottom flask was combined
  2. customThe flask was flushed with nitrogen gas
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationThe mixture was filtered through an Empore™ cartridge
  5. customthe solvents removed
  6. customthe product purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm
  7. wait5% acetonitrile-0.1M ammonium acetate isocratic for 5 minutes
  8. wait5-100% acetonitrile-0.1M ammonium acetate over 30 min
  9. customThe acetonitrile was removed

Sources & evidence

ORD record
ord-315ee4eb6f794fd0b0d99693245d68a7
Source dataset
uspto-grants-2012_09
Patent number
US08273736B2

Reaction notes

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