Water → HCID 66605794, compound

HRID 2410888Notes

Reaction equation

HRID 2410888 reaction equation
Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:21](=[C:22]([C:24](=[O:26])[NH2:25])[CH:23]=2)[NH:20][C:19]2[CH:18]=[C:17]([N:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:16]=[CH:15][C:14]3=2)=[CH:7][C:6]=1[Cl:40].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:6]([Cl:40])[CH:7]=2)[CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[CH:18]=[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:16]=[CH:15][C:14]2=1)(=[O:26])[NH2:25]

Participants

6

Reactant 4

HCID 962WaterHCID 8083MorpholineHCID 11430Potassium CarbonateHCID 66604616HCID 66604616, compound

Product 1

HCID 66605794HCID 66605794, compoundYield 89.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

tert-Butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (342 mg, estimated purity 55%, ˜0.30 mmol, Example 409C) was dissolved in DMF (6 ml). Morpholine (0.5 ml, 5.7 mmol) and K2CO3 (160 mg, 1.16 mmol) were added and the mixture heated to 75° C. for 2 hour. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+25 ml saturated aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. Purification by prep HPLC gave 170 mg tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-(2-morpholinoethoxy)phenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate. MS (ESI) m/e+=634/636, m/e−=632/634 [1 Cl isotope pattern]. HPLC retention time 16.96 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.50 (d, 1H, J=1.3), 8.33 (b, 1H), 8.14 (d, 1H, J=1.5), 8.07 (d, 1H, J=8.8), 7.98 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.8, 2.3), 7.51 (b, 1H), 7.31 (d, 1H, J=8.8), 7.25 (d, 1H, J=2.0), 6.95 (dd, 1H, J=8.8, 2.0), 4.26 (t, 2H, J=5.8), 3.63-3.59 (m, 4H), 3.53 (b, 4H), 3.21-3.17 (m, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H), 1.46 (s, 9H).

Workup

  1. additionThe reaction mixture was poured into a separating funnel that
  2. extractionextracted with ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated to dryness
  7. customPurification by prep HPLC

Sources & evidence

ORD record
ord-2658414398aa4f009f503fcea10f6e39
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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