Trifluoroacetic acid → 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid

HRID 350894Notes

Reaction equation

[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30].[OH-].[Na+].O1CCOCC1.FC(F)(F)C(O)=O>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([OH:14])=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]

Participants

Conditions

Temperature: 55 °C

Procedure

A mixture of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.40 g, 0.00084 mol, from Step 4), and 1.5 N NaOH (0.7 mL, 0.042 g, 0.001 mol) containing dioxane (0.5 mL) is stirred at 55° C. for 30 min. The resulting clear brown solution is cooled in an ice bath, diluted with water (3 mL), acidified with trifluoroacetic acid, and the product is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=465) are combined and freeze-dried to afford the title compound (0.17 g, 44%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.6 Hz), 7.54 (m, 2H), 6.99 (m 2H), 5.56 (s, 2H), 2.15 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 465.0256 (M+H calcd for C20H16N2O4F2Br requires 465.0256); 19F NMR(CD3OD/400 MHz) −111.89 (m) and −115.95 (m).

Workup

temperatureThe resulting clear brown solution is cooled in an ice bath
customthe product is purified by reverse-phase
custom10–90% CH3CN/Water gradient (40 min)
customfreeze-dried

Sources & evidence

ORD record: ord-58a1fce2e9564bc286e3fc114bd764c8
Source dataset: uspto-grants-2007_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07183287B2

Reaction notes

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