Dimethylformamide → 5-(4-(1H-Indazol-5-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

HRID 1487923Notes

Reaction equation

HRID 1487923 reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:3][CH2:2]1.CN(C)C=O.[CH:21]1([C:25]2[C:33]([C:34](=[O:37])[NH:35][CH3:36])=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([CH3:38])[CH:26]=2)[CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:29]([C:28]4[C:27]([CH3:38])=[CH:26][C:25]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[C:33]([CH:32]=4)[C:34]([NH:35][CH3:36])=[O:37])=[O:30])[CH2:6][CH2:5]3)=[CH:15][CH:14]=2)[CH:10]=[N:11]1

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 497608595-(Piperidin-4-YL)-1H-indazole2×HCID 900220514-Cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid2×

Product 1

HCID 900332645-(4-(1H-Indazol-5-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamideYield 33.7%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolvent

Procedure

Into a 50-mL round-bottom flask, was placed a solution of 5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL) EDC.HCl (192 mg, 1.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 122 mg, 0.49 mmol) were added and the resulting solution was stirred for 4 h at room temperature. The reaction was diluted with water (20 mL) and extracted with of ethyl acetate (2×25 mL). The combined organic layers were washed with brine (2×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent, followed by additional purification by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 47% in 7 min, up to 100% in 3 min, down to 30% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (71.2 mg, 33%). m/z (ES+) 431 (M+H)+.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. extractionextracted with of ethyl acetate (2×25 mL)
  3. washThe combined organic layers were washed with brine (2×15 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography with ethyl acetate as the eluent
  8. customfollowed by additional purification by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  9. waitmobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 47% in 7 min
  10. waitup to 100% in 3 min
  11. waitdown to 30% in 1 min)
  12. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-cb2777dcfa084b55acc7c50c707524cb
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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