Acrylic Acid → N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide

HRID 1522090Notes

Reaction equation

HRID 1522090 reaction equation
[C:1](O)(=[O:4])[CH:2]=[CH2:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=1)[O:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:44][CH:43]=1>O1CCOCC1>[NH2:41][C:37]1[N:38]=[CH:39][N:40]=[C:35]([O:34][C:33]2[CH:32]=[C:31]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:57]=[CH:56][CH:55]=2)[C:36]=1[C:42]1[CH:43]=[CH:44][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:46][CH:47]=1

Participants

6

Reactant 4

HCID 6581Acrylic AcidHCID 81531DiisopropylethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 867217356-(3-Aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine

Product 1

HCID 71473954N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamideYield 85.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

Into a 20 mL reaction vial was added acrylic acid (0.01 ml; 0.12 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42.04 mg; 0.17 mmol), and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at rt for 1 h. 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08 mmol) was then added. The reaction mixture was stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was then purified using preparative HPLC eluting from 35-45% CH3CN in 0.1% TFA in H2O. fractions containing the desired product were combined and lyophilized overnight to afford N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide as a white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264 min. MS: m/z=425 [M+H]+, RT=2.14 min. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

Workup

  1. customInto a 20 mL reaction
  2. stirringThe reaction mixture was stirred at rt overnight
  3. customThe crude mixture was purified
  4. washeluting from 50-100% EtOAc/Hexanes
  5. additionFractions containing the desired product
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was then purified
  8. washeluting from 35-45% CH3CN in 0.1% TFA in H2O
  9. additionfractions containing the desired product
  10. waitlyophilized overnight

Sources & evidence

ORD record
ord-4d7fa3a9122c4b9bb0aaa5992cc97910
Source dataset
uspto-grants-2015_07
Patent number
US09073947B2

Reaction notes

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