Triisopropyl phosphite → Dipropan-2-yl(3-nitrobenzyl)phosphonate
Reaction equation
[P:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])[O:2]C(C)C.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>>[CH3:13][CH:11]([O:10][P:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)(=[O:2])[O:6][CH:7]([CH3:8])[CH3:9])[CH3:12]Participants
Conditions
- Temperature
- 100 °C
Procedure
A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl(3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl(3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl[3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6H), 1.28 (d, J=6.1 Hz, 6H), 3.06-3.12 (m, 4H), 3.12-3.19 (m, 4H), 4.51-4.63 (m, 2H), 4.96 (s, 2H), 7.14 (d, J=7.3 Hz, 1H), 7.21-7.28 (m, 1H), 7.29-7.33 (m, 1H), 7.35-7.43 (m, 2H), 7.76 (d, J=7.6 Hz, 1H), 8.21 (s, 1H), 8.45 (dd, J=4.8, 1.8 Hz, 1H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).
Sources & evidence
- ORD record
- ord-dab393f08ad148c2b3349a8f95820476
- Source dataset
- uspto-grants-2013_03
- Patent number
- US08399433B2
Reaction notes
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