Dimethylformamide → Selonsertib

HRID 522476Notes

Reaction equation

HRID 522476 reaction equation
Cl.[CH:2]1([C:5]2[N:6]=[CH:7][N:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([F:19])=[C:14]([CH:18]=3)[C:15]([OH:17])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:32]([N:35]1[CH:39]=[N:38][N:37]=[C:36]1[C:40]1[N:45]=[C:44]([NH2:46])[CH:43]=[CH:42][CH:41]=1)([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][N:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([F:19])=[C:14]([CH:18]=3)[C:15]([NH:46][C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:36]4[N:35]([CH:32]([CH3:34])[CH3:33])[CH:39]=[N:38][N:37]=4)[N:45]=3)=[O:17])[CH:9]=2)[CH2:3][CH2:4]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 815728386-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine2×HCID 866912505-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride

Product 1

HCID 71245288Selonsertib

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (1.5 g, 5.07 mmol) was suspended in anhydrous 1,2-dichloromethane (25 mL) at room temperature. Oxalyl chloride (0.575 ml, 6.59 mmol) was added with stirring under nitrogen, followed by N,N-dimethylformamide (0.044 ml, 0.507 mmol). The mixture was stirred for 4 hr at room temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in 25 mL anhydrous dichloromethane. 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (1.13 g, 5.58 mmol) (compound C) and 4-dimethylaminopyridine (0.62 g, 5.07 mmol) were rapidly added with stirring under nitrogen. The reaction was stirred for 2 hours at room temperature and aqueous saturated NaHCO3 (15 mL) was added. The mixture was stirred for 10 minutes, and the layers were separated, and the aqueous layer was washed 1×20 mL dichloromethane. The combined organics were dried (MgSO4), filtered and concentrated. The residue was dissolved in a minimum amount of CH3CN and water was slowly added until solids precipitated from the mixture. The solid was collected by filtration and dried to give 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide in ˜96% purity (1.28 g, 2.88 mmol). Anal. LC/MS (m/z: 446, M+1). The material was further purified by RP-HPLC (reverse phase HPLC) to obtain an analytically pure sample as the HCl salt.

Workup

  1. stirringThe mixture was stirred for 4 hr at room temperature
  2. customthe solvent was removed under reduced pressure
  3. dissolutionThe residue was dissolved in 25 mL anhydrous dichloromethane
  4. stirringwith stirring under nitrogen
  5. stirringThe reaction was stirred for 2 hours at room temperature
  6. stirringThe mixture was stirred for 10 minutes
  7. customthe layers were separated
  8. washthe aqueous layer was washed 1×20 mL dichloromethane
  9. dry with materialThe combined organics were dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. dissolutionThe residue was dissolved in a minimum amount of CH3CN and water
  13. additionwas slowly added until solids
  14. customprecipitated from the mixture
  15. filtrationThe solid was collected by filtration
  16. customdried

Sources & evidence

ORD record
ord-f87a164f827547c29305b143914fe143
Source dataset
uspto-grants-2016_05
Patent number
US09333197B2

Reaction notes

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