Ethanol → Ethyl hydrogen 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate

HRID 348212Notes

Reaction equation

HRID 348212 reaction equation
[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:40])([O:37]CC)[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:37])([OH:40])[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 702EthanolHCID 14798Sodium HydroxideHCID 21069942Diethyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate

Product 1

HCID 21069963Ethyl hydrogen 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonateYield 64.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

A solution of intermediate 187, diethyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate (0.115 g, 0.20 mmol) in tetrahydrofuran (3 ml)/ethanol (3 mL) was treated with 1 N aqueous sodium hydroxide (1.0 ml, 1.0 mmol) and the resulting mixture heated at 45° C. for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a Shimadzu automated preparative HPLC system (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.070 g (64% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ ppm: 1.37 (3H, t, J=7.1 Hz, CH3), 1.62 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.18 (2H, m, OCH2), 4.75 (2H, broad d, J=5 Hz, NCH2), 5.32 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.30–7.33 (3H, m, aromatics), 7.38–7.40 (2H, m, aromatics), 7.47–7.52 (1H, m, aromatic), 7.56–7.63 (1H, m, aromatic), 8.56 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN3O7P [M+H+]: 546.1805. Found: 546.1786.

Workup

  1. washwashed with 0.1 N hydrochloric acid, brine
  2. dry with materialdried over anhydrous magnesium sulfate
  3. concentrationconcentrated
  4. customThe residue was purified on a Shimadzu
  5. washHPLC system (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-9eb96ca868b7447cad1feb0b15a075c9
Source dataset
uspto-grants-2007_02
Patent number
US07176196B2

Reaction notes

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