Lithium diisopropylamide → Diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate

HRID 2167649Notes

Reaction equation

HRID 2167649 reaction equation
[F:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[F:3].[Li+].CC([N-]C(C)C)C.[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]=[O:47])=[CH:45][C:23]=2[N:22]=1>C1COCC1>[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]([OH:47])[C:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])([F:3])[F:1])=[CH:45][C:23]=2[N:22]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 2758305Phosphonic acid, (difluoromethyl)-, diethyl esterHCID 581665185-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde

Product 1

HCID 86651451Diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of diethyl difluoromethylphosphonate (3.0 equiv.) in THF (0.3 M) at −78° C. under nitrogen atmosphere was added dropwise 2M LDA (3.0 equiv., commercial grade). The reaction was stirred at −78° C. for 25 min, and a solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (1.0 equiv.) in THF (0.1 M) was added slowly. The reaction was stirred at −78° C. for 1 hour, 0° C. for 1 hour, and then warmed to room temperature over 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate (2-3) as a solid.

Workup

  1. stirringThe reaction was stirred at −78° C. for 1 hour, 0° C. for 1 hour
  2. temperaturewarmed to room temperature over 30 minutes
  3. customThe reaction was quenched with saturated aqueous ammonium chloride solution
  4. extractionextracted twice with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over anhydrous MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by a COMBIFLASH® system (ISCO)

Sources & evidence

ORD record
ord-4043b6ab37514e7e824747c1a8576722
Source dataset
uspto-grants-2015_06
Patent number
US09045470B2

Reaction notes

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