Water → HCID 178522484, compound

HRID 2098248Notes

Reaction equation

HRID 2098248 reaction equation
[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:7][CH2:6][C@@H:2]6[CH2:3][CH2:4][CH2:5][O:1]6)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1

Participants

5

Reactant 3

HCID 962WaterHCID 637528(2S)-(+)-2-(Hydroxymethyl)tetrahydrofuranHCID 178522482HCID 178522482, compound

Product 1

HCID 178522484HCID 178522484, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-(tetrahydrofuran-2-yl-)-methanol (30.6 mg) in dry DMF (1 mL) NaH (12 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. To this mixture 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (44.0 mg) was added, and the mixture was warmed to 80° C. The reaction was monitored by LCMS until substantially complete. Then, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product 6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (24.8 mg) was purified by column chromatography (prepacked silica column) using 9:1 DCM and 2N ammonia in methanol. LCMS (m/z): 507.9. 1H NMR (400 MHz, CDCl3) δ 11.23 (1H, br. s.) 10.25-10.73 (1H, m) 8.40 (1H, s) 7.74 (2H, d) 7.38-7.44 (2H, m) 7.19-7.25 (2H, m) 7.04 (1H, dt) 6.83-6.89 (1H, m) 4.24-4.42 (3H, m) 3.82-4.03 (2H, m) 1.91-2.17 (2H, m) 1.67-1.82 (2H, m).

Workup

  1. temperaturethe mixture was warmed to 80° C
  2. stirringthe reaction mixture was stirred for 10 minutes
  3. filtrationThe reaction was then filtered through a fine fritted funnel
  4. washthe crude product was washed with water
  5. customAfter air drying
  6. customthe product 6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (24.8 mg) was purified by column chromatography (prepacked silica column)

Sources & evidence

ORD record
ord-4da6ac3b65f74900a04fc9bf31cfd999
Source dataset
uspto-grants-2013_05
Patent number
US08450354B2

Reaction notes

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