Diisopropylethylamine → 2-(4-(1,4-Dimethylpiperidin-4-yl)phenylamino)-5-fluoro-6-(3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-en-7-yl)nicotinamide

HRID 2044108Notes

Reaction equation

HRID 2044108 reaction equation
Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([CH3:26])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:27]1([C:33]2[CH2:37][C:36]3([CH2:42][CH2:41][CH2:40][NH:39][CH2:38]3)[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:4]3[N:3]=[C:2]([N:39]4[CH2:40][CH2:41][CH2:42][C:36]5([O:35][N:34]=[C:33]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:37]5)[CH2:38]4)[C:10]([F:11])=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:14][CH:15]=2)([CH3:26])[CH2:20][CH2:21]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 569344603-Phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-eneHCID 574896566-Chloro-2-(4-(1,4-dimethylpiperidin-4-yl)phenylamino)-5-fluoronicotinamide

Product 1

HCID 498472852-(4-(1,4-Dimethylpiperidin-4-yl)phenylamino)-5-fluoro-6-(3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-en-7-yl)nicotinamideYield 20.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A solution of 6-chloro-2-(4-(1,4-dimethylpiperidin-4-yl)phenylamino)-5-fluoronicotinamide (40 mg, 0.106 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene (42.1 mg, 0.127 mmol), and DIEA (0.074 mL, 0.425 mmol) in NMP (1 mL) was heated at 120° C. for 3 h and at 130° C. for 2 h. The reaction mixture was cooled, diluted with water. The resulting brown solid precipitate was filtered and purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic factions were washed with water and concentrated to give 12 mg yellow solid. LC-MS: 3.04 min (RT). (M+H)+=557.28. 1H NMR (400 MHz, chloroform-d) δ ppm 10.66 (1H, s), 7.67 (2H, dd, J=6.81, 2.86 Hz), 7.50 (2H, d, J=8.79 Hz), 7.36-7.44 (3H, m), 7.22-7.25 (1H, m), 7.13 (2H, d, J=8.79 Hz), 5.43 (2H, br. s.), 3.79-3.90 (2H, m), 3.69-3.75 (1H, m), 3.57-3.67 (1H, m), 3.32 (1H, d, J=16.70 Hz), 3.05 (1H, d, J=16.70 Hz), 2.27-2.45 (4H, m), 2.22 (3H, s), 1.92-2.13 (4H, m), 1.57-1.79 (4H, m), 1.12 (3 H, s).

Workup

  1. temperatureThe reaction mixture was cooled
  2. filtrationThe resulting brown solid precipitate was filtered
  3. custompurified by prep-HPLC
  4. additionThe product containing fractions
  5. customwere collected
  6. extractionextracted with methylene chloride twice
  7. washThe combined organic factions were washed with water
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-06d5ddf6a94e4947bbe672bbc876877a
Source dataset
uspto-grants-2013_11
Patent number
US08586751B2

Reaction notes

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