Chloroacetyl chloride → HCID 67256382, compound

HRID 1509122Notes

Reaction equation

HRID 1509122 reaction equation
[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:44](=[O:45])[CH2:43][O:31][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 178452604HCID 178452604, compound

Product 1

HCID 67256382HCID 67256382, compoundYield 42%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.8 g, 4.17 mmol), DIPEA (3.63 ml, 20 mmol) in DCM (100 ml) at 0° C. was added a solution of chloroacetyl chloride (0.465 ml) in DCM (20 ml). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added MIBK (120 ml) and saturated sodium bicarbonate (120 ml). The resulting mixture was heated at 115° C. for 16 h. After cooled down to room temperature, the MIBK was removed under reduced pressure. The residue was extracted with ethyl acetate (75 ml). The layers were separated and the aqueous phase extracted into ethyl acetate (2×50 ml). The combined organic phases were washed with water (150 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% methanol in DCM) to give the title compound (0.82 g, 42%). LCMS (Method A): RT=6.55 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.3-7.0 (10H, m), 4.96 (1H, br), 4.82 (2H, s), 2.55-2.25 (4H, m), 2.1-1.9 (1H, m), 1.8-1.65 (1H, m), 1.35-1.1 (9H, br).

Workup

  1. concentrationThe reaction mixture was concentrated to dryness under reduced pressure
  2. additionTo the residue was added MIBK (120 ml) and saturated sodium bicarbonate (120 ml)
  3. temperatureThe resulting mixture was heated at 115° C. for 16 h
  4. temperatureAfter cooled down to room temperature
  5. customthe MIBK was removed under reduced pressure
  6. extractionThe residue was extracted with ethyl acetate (75 ml)
  7. customThe layers were separated
  8. extractionthe aqueous phase extracted into ethyl acetate (2×50 ml)
  9. washThe combined organic phases were washed with water (150 ml) and brine (150 ml)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated to dryness under reduced pressure
  13. customThe resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% methanol in DCM)

Sources & evidence

ORD record
ord-9814d64dac9748acbaf894e15b286357
Source dataset
uspto-grants-2015_12
Patent number
US09221838B2

Reaction notes

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