Trifluoroacetic acid → Diethyl (4-{[4-({7-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 2279698Notes

Reaction equation

HRID 2279698 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[CH:32]=[CH:33][C:34]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][CH2:49][OH:50])[CH:46]=2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[OH:50][CH2:49][CH2:48][CH2:47][N:45]1[CH:46]=[C:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[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]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH:43]=[N:44]1

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 672551227-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one2×HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate2×

Product 1

HCID 58292892Diethyl (4-{[4-({7-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Conditions

Temperature
0 °C

Procedure

A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1E, 897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 1C, 634 mg, 2.21 mmol) in TFE (12 mL) was charged with TFA (654 mg, 5.74 mmol) and irradiated in a microwave reactor for 1 h at 105° C. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue, dissolved in MeOH and cooled to 0° C., was charged with 7.0 M of NH3 in MeOH (5 mL) and then warmed to rt over 2 h. The suspension was concentrated in vacuo and purified using a Teledyne ISCO CombiFlash® Rf system (eluting with 0-10% MeOH:CH2Cl2) to isolate the desired compound as 1.10 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.10 (br. t, J=2.0 Hz, 1H), 6.96 (br td, J=2.3, 8.0 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.1, 8.1 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.1 Hz, 2H), 3.36 (d, J=20 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.6 Hz, 2H), 1.17 (t, J=7 Hz, 6H). MS (ESI): m/z 704.23 (100) [M+H]+. HPLC: tR=3.73 min (ZQ3: polar—5 min).

Workup

  1. customirradiated in a microwave reactor for 1 h at 105° C
  2. customThe reaction mixture was transferred to a round bottom flask
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue, dissolved in MeOH
  5. additionwas charged with 7.0 M of NH3 in MeOH (5 mL)
  6. temperaturewarmed to rt over 2 h
  7. concentrationThe suspension was concentrated in vacuo
  8. custompurified
  9. washa Teledyne ISCO CombiFlash® Rf system (eluting with 0-10% MeOH:CH2Cl2)

Sources & evidence

ORD record
ord-757b7c27906940a98e095cea913fef73
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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