Bromotrimethylsilane → (E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid

HRID 2167657Notes

Reaction equation

HRID 2167657 reaction equation
[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:28](/[P:30](=[O:37])([O:34]CC)[O:31]CC)\[F:29])=[CH:26][C:4]=2[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:28](/[P:30](=[O:31])([OH:34])[OH:37])\[F:29])=[CH:26][C:4]=2[N:3]=1

Participants

4

Reactant 2

HCID 76113BromotrimethylsilaneHCID 86651455(E)-Diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonate

Product 1

HCID 49838509(E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonate (3-2) (1.0 equiv.) in DCM (0.05 M) at 0° C. was added TMSBr (10 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then DMSO/water was added. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give (E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid (12) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.80 (s, 1H), 9.41 (s, 1H), 9.05 (s, 1H), 8.87 (s, 1H), 8.65 (d, 1H, J=8.8 Hz), 8.08 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.02 (d, 1H, J=8.4 Hz), 6.83-6.65 (m, 2H), 3.69 (s, 3H), 3.18-3.12 (m, 2H), 3.02-2.96 (m, 4H), 2.28 (s, 3H). LRMS [M+H]=468.1

Workup

  1. customquenched with small amounts of MeOH
  2. customThe DCM was removed by evaporation
  3. additionDMSO/water was added
  4. customdirectly purified on RP-HPLC
  5. washeluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient
  6. additionThe fractions containing the product
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0e2da2a4cbe54612b4d638f2eb593016
Source dataset
uspto-grants-2015_06
Patent number
US09045470B2

Reaction notes

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