Sodium hydride → (6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

HRID 1099181Notes

Reaction equation

HRID 1099181 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:16]=[C:11]2[CH2:10]1.[H-].[Na+].[O:26]=[C:27]1[NH:35][C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]1[CH:36]1[CH2:41][CH2:40][N:39]([C:42](OC2C=CC([N+]([O-])=O)=CC=2)=[O:43])[CH2:38][CH2:37]1>C1COCC1>[O:26]=[C:27]1[NH:35][C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]1[CH:36]1[CH2:37][CH2:38][N:39]([C:42]([O:23][C@H:20]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:16]=[C:11]3[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:22][CH2:21]2)=[O:43])[CH2:40][CH2:41]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 579114044-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylateHCID 57911469(6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol2×

Product 1

HCID 57911425(6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylateYield 40.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(6R,9R)-6-(2,3-Difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) with stirring bar was azeotroped by benzene. Sodium hydride (20.80 mg, 0.867 mmol) was added to the THF (3 mL) suspension of (6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (43.2 mg, 0.113 mmol) at rt. The reaction was stirred at this temperature overnight. The reaction was quenched by water and partitioned between ethyl acetate and water. The ethyl acetate layer was washed by water two more times before dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 4% to 8% gave the desired product (19.8 mg, 36%). MS (ESI)[M+H+]=563.35; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.30 (br. s., 1H) 8.08 (d, J=5.49 Hz, 1 H) 7.95-8.05 (m, 1H) 7.37-7.53 (m, 1H) 6.94-7.14 (m, 4H) 6.79 (br. s., 1H) 6.00 (d, J=10.38 Hz, 1H) 4.66 (br. m., 3H) 3.32 (t, J=12.67 Hz, 1H) 3.08 (br. m., 2 H) 2.91-3.02 (m, 6H) 2.29 (d, J=13.73 Hz, 2H) 2.13-2.24 (m, 2H) 1.86-2.07 (m, 2H) 1.20-1.40 (m, 3H) 0.75-0.98 (m, 1H).

Workup

  1. customwas azeotroped by benzene
  2. customThe reaction was quenched by water
  3. custompartitioned between ethyl acetate and water
  4. washThe ethyl acetate layer was washed by water two more times
  5. dry with materialbefore dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-4e2ba99fb3ed4398bde2789672624606
Source dataset
uspto-grants-2012_03
Patent number
US08143403B2

Reaction notes

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