Trifluoroacetic acid → Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 1947849Notes

Reaction equation

HRID 1947849 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:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34].C(O)(C(F)(F)F)=O>>[F:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[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]=3[O:28][CH3:29])[N:3]=2)=[C:32]([C:33](=[O:34])[NH:35][CH3:36])[CH:37]=1

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 431325582-Amino-5-fluoro-N-methylbenzamide2×HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Product 1

HCID 49822431Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonateYield 33%

Procedure

A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and 2-amino-5-fluoro-N-methylbenzamide (Compound 102A, 22.24 mg, 0.1322 mmol) in TFE (1.00 mL) was charged with TFA (37.7 mg, 0.330 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0->95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 21.4 mg (33% yield). The material still contained impurities, therefore was submitted for mass directed purification. The fractions containing product were combined and dried on the freeze dryer to yield a white solid, 10.9 mg (17% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.76 (d, J=4.55 Hz, 3H), 3.21-3.28 (m, 2H), 3.76 (s, 3H), 3.92-4.04 (m, 4H), 6.84 (d, J=6.57 Hz, 1H), 7.01 (br. s., 1H), 7.24 (br. s., 1H), 7.38-7.65 (m, 2H), 8.24-8.55 (m, 2H), 8.79 (br. s., 2H), 11.25 (br. s., 1H). MS (ES+): m/z 586.19 [MH+] (TOF, polar)

Workup

  1. customThe reaction mixture was irradiated on the microwave at 105° C. for 1 hour
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customto yield a yellow oil
  4. customThe material was purified by silica gel chromatography on an ISCO Combi-flash Rf system
  5. additionThe fractions containing product
  6. concentrationconcentrated under reduced pressure
  7. customto yield a white solid, 21.4 mg (33% yield)
  8. custompurification
  9. additionThe fractions containing product
  10. customdried on the freeze dryer
  11. customto yield a white solid, 10.9 mg (17% yield)

Sources & evidence

ORD record
ord-e56a64b6a7e3440a8278d8041ea4510f
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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