Water → 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide

HRID 2098240Notes

Reaction equation

HRID 2098240 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@H:41]([CH3:44])[CH2:42][OH:43].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 9793900(2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-olHCID 1785224796-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide

Product 1

HCID 1784623606-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) in dry DMF (1 mL) was added NaH (40 mg, dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. Then, water (10 mL) was added and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and dissolved in 1:1 mixture of methanol and DCM (5 mL). To this was added 2 M solution of hydrochloric acid in methanol (1 mL) and stirred at room temperature for 2 h. After air drying, the product was purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (37 mg). LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.15 (1H, d) 7.92 (1H, brs) 7.87-7.93 (3H, m) 7.55-7.63 (2H, m) 7.08 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.03-4.07 (1H, m) 1.18 (3H, d).

Workup

  1. stirringthe reaction mixture stirred for 10 minutes
  2. filtrationThe precipitated solid was filtered
  3. dissolutiondissolved in 1:1 mixture of methanol and DCM (5 mL)
  4. additionTo this was added 2 M solution of hydrochloric acid in methanol (1 mL)
  5. stirringstirred at room temperature for 2 h
  6. customAfter air drying
  7. customthe product was purified by column chromatography (12 g pre-packed silica gel column cartridge)

Sources & evidence

ORD record
ord-2f0a5a4062ae48528e58be2faebc6ca5
Source dataset
uspto-grants-2013_05
Patent number
US08450354B2

Reaction notes

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