Trifluoroacetic acid → Diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

HRID 511472Notes

Reaction equation

HRID 511472 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[C:32]([C:37]([NH:39][CH3:40])=[O:38])=[N:33][CH:34]=[CH:35][CH:36]=1.C(O)(C(F)(F)F)=O>O>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[C:32]([C:37](=[O:38])[NH:39][CH3:40])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 135332483-Amino-N-methylpicolinamide2×HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Product 1

HCID 58293023Diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol) and 3-amino-N-methylpyridine-2-carboxamide (Compound 231C, 15.0 mg, 0.0992 mmol) were taken up in TFE (2.7 mL, 37 mmol) and treated with TFA (15.3 uL, 0.198 mmol). This mixture was irradiated on the CEM for 120 min at 100° C. Rxn mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 20.8 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.07 Hz, 6H), 2.81 (d, J=4.80 Hz, 3H), 3.28 (d, J=20.50 Hz, 2H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 6.90 (dt, J=8.15, 1.99 Hz, 1H), 7.05 (s, 1H), 7.33-7.51 (m, 2H), 8.21 (d, J=3.54 Hz, 1H), 8.41 (s, 1H), 9.08 (br. s., 1H), 9.11 (q, J=4.21 Hz, 1H), 12.45 (s, 1H). MS (ES+): m/z=569.10 (100) [M+1]. HPLC: tR=1.52 min (UPLC TOF, polar—3 min).

Workup

  1. customThis mixture was irradiated on the CEM for 120 min at 100° C
  2. extractionextracted twice with EtOAc
  3. dry with materialThe combined organic layers were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM)
  7. customto isolate
  8. concentrationafter concentrating the relevant fractions
  9. customdrying in vacuo
  10. customHPLC: tR=1.52 min (UPLC TOF, polar—3 min)

Sources & evidence

ORD record
ord-679fc4f551f04d38abd5de299f065f95
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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