N-methyl-2-pyrrolidone → rel-11-[(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide

HRID 70798Notes

Reaction equation

HRID 70798 reaction equation
Cl.[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.Cl[C:30]1[N:38]2[C:34](=[N:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=32)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]2[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=12>O>[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5]([C:30]2[N:38]3[C:34](=[N:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=43)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]3[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=23)[CH2:4]1

Participants

6

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 8941387611-chloro-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamideHCID 89413909rel-[(3R,4S)-3-fluoro-4-methoxypiperidin-4-yl]methanol hydrochloride

Product 1

HCID 54588431rel-11-[(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamideYield 38.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

rel-[(3R,4S)-3-fluoro-4-methoxypiperidin-4-yl]methanol hydrochloride (399 mg) and DIPEA (523 μl) were added to an NMP (3 ml) solution of 11-chloro-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (314 mg), and heating and stirring were performed at 200° C. for 60 minutes under microwave irradiation. After adding water to the reaction liquid, the resulting precipitate was collected by filtration and dried under reduced pressure. The resulting solid was purified by silica gel column chromatography (MeOH/chloroform). The resulting crude purified matter was washed with chloroform-EtOAc-hexane to obtain rel-11-[(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (169 mg).

Workup

  1. temperatureheating
  2. customwere performed at 200° C. for 60 minutes under microwave irradiation
  3. customto the reaction liquid
  4. filtrationthe resulting precipitate was collected by filtration
  5. customdried under reduced pressure
  6. customThe resulting solid was purified by silica gel column chromatography (MeOH/chloroform)
  7. customThe resulting crude purified matter
  8. washwas washed with chloroform-EtOAc-hexane

Sources & evidence

ORD record
ord-2e9ce635640d40b0acc324e8d119694a
Source dataset
uspto-grants-2014_09
Patent number
US08822688B2

Reaction notes

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