4-Methylmorpholine → rac-8-[(2,6-Difluorobenzyl)oxy]-2-methyl-N-(1,1,1-trifluoro-3-hydroxypropan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide

HRID 1844205Notes

Reaction equation

HRID 1844205 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[N:47]1CC[O:50][CH2:49][CH2:48]1.NC(C[C:58]([F:61])([F:60])[F:59])CO>ClCCl.CN(C=O)C>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:47][CH:48]([CH2:49][OH:50])[C:58]([F:61])([F:60])[F:59])=[O:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 534164332-Amino-4,4,4-trifluorobutan-1-ol4×HCID 867178728-((2,6-Difluorobenzyl)oxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acidHCID 178484679HCID 178484679, compound

Product 1

HCID 90115599rac-8-[(2,6-Difluorobenzyl)oxy]-2-methyl-N-(1,1,1-trifluoro-3-hydroxypropan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

50 mg (0.16 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 55 mg (0.17 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 79 mg (0.79 mmol) of 4-methylmorpholine were initially charged in 1.0 ml of dichloromethane. After 10 min at RT, 28 mg (0.17 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were added and the mixture was stirred at room temperature overnight. 1 ml of DMF and 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were then added, and the mixture was stirred at 50° C. for 8 h. Another 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were added, and the mixture was stirred in a microwave at 80° C. for 0.5 h. Another 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were then added, and the mixture was stirred in a microwave at 80° C. for 1 h. The reaction solution was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. This gave 17 mg of the target compound (25% of theory, purity 100%).

Workup

  1. stirringthe mixture was stirred at 50° C. for 8 h
  2. stirringthe mixture was stirred in a microwave at 80° C. for 0.5 h
  3. stirringthe mixture was stirred in a microwave at 80° C. for 1 h
  4. concentrationThe reaction solution was concentrated
  5. custompurified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA)
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in dichloromethane
  8. washwashed with saturated aqueous sodium bicarbonate solution

Sources & evidence

ORD record
ord-3b954f6e4093445bbe4fa1b56affed04
Source dataset
uspto-grants-2015_02
Patent number
US08946215B2

Reaction notes

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