Diisopropyl Phosphorochloridate → 5-((4-(3-Acrylamidophenyl)-5-Chloropyrimidin-2-Yl)Amino)-2-Morpholinophenyl Diisopropyl Phosphate

HRID 929692Notes

Reaction equation

HRID 929692 reaction equation
C([Li])CCC.[Cl:6][C:7]1[C:8]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:16]([OH:26])[CH:15]=2)=[N:11][CH:12]=1.[P:38](Cl)(=[O:47])([O:43][CH:44]([CH3:46])[CH3:45])[O:39][CH:40]([CH3:42])[CH3:41]>C1COCC1>[P:38]([O:43][CH:44]([CH3:46])[CH3:45])([O:39][CH:40]([CH3:42])[CH3:41])([O:26][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[N:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:28]=3)[C:7]([Cl:6])=[CH:12][N:11]=2)[CH:19]=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:47]

Participants

5

Reactant 3

HCID 164989Diisopropyl PhosphorochloridateHCID 73438564N-(3-(5-Chloro-2-((3-Hydroxy-4-Morpholinophenyl)Amino)Pyrimidin-4-Yl)Phenyl)AcrylamideHCID 178418339Butyllithium

Product 1

HCID 736693375-((4-(3-Acrylamidophenyl)-5-Chloropyrimidin-2-Yl)Amino)-2-Morpholinophenyl Diisopropyl PhosphateYield 35.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

n-Butyl lithium (0.14 mL, 2.5 M solution in hexane) was diluted 10-fold in THF (1.4 mL), and the resulting mixture added dropwise to a rapidly stirring solution of N-(3-(5-chloro-2-((3-hydroxy-4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.221 mmol) in THF (5 ml) that was under argon gas and the reaction vessel was immersed in a salt-ice bath (bath temperature about −10° C. to −5° C.). The resulting white suspension was stirred for 5 min, followed by addition of diisopropyl phosphorochloridate (178 mg, 0.885 mmol) to the reaction mixture in a single portion. The suspension became a clear solution within about 5 min, and then reaction mixture was stirred at ambient temperature for about 18 h. Then reaction mixture was evaporated to dryness on a rotary evaporator. The resulting crude residue was purified by silica gel flash chromatography using a mixture of 3% methanol and DCM as eluting solvent to provide the title compound (50 mg, 0.078 mmol, 35.2% yield) as a syrup. 1HNMR (400 MHz, CDCl3): δ 8.52 (bs, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.37 (s, 1H), 7.98 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.38 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=8.0 Hz), 6.45 (m, 2H), 5.68 (t, 1H, J=6.0 Hz), 4.74 (m, 2H), 3.81 (m, 4H), 2.96 (m, 4H). Mass: 616.2 [M+H]+.

Workup

  1. customthe reaction vessel was immersed in a salt-ice bath
  2. custom(bath temperature about −10° C. to −5° C.)
  3. customwithin about 5 min
  4. customreaction mixture
  5. stirringwas stirred at ambient temperature for about 18 h
  6. customThen reaction mixture
  7. customwas evaporated to dryness on a rotary evaporator
  8. customThe resulting crude residue was purified by silica gel flash chromatography
  9. additiona mixture of 3% methanol and DCM
  10. washas eluting solvent

Sources & evidence

ORD record
ord-dfa03c79dd714ed4a05cc49c907e83ac
Source dataset
uspto-grants-2016_03
Patent number
US09296703B2

Reaction notes

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