Diisopropylethylamine → 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

HRID 1726646Notes

Reaction equation

HRID 1726646 reaction equation
[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)C(C)C)(C)C.[P:43]([O-:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>C(O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

8

Reactant 3

HCID 81531DiisopropylethylamineHCID 3780918DiethylphosphiteHCID 21070019N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide

Product 1

HCID 21069942Diethyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonateYield 51.3%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 167845palladium(II) acetateCatalystHCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml) was flushed with argon and then treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol), palladium(11) acetate (0.020 g) and diethyl phosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed and heated at 80° C. for 18 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of acetonitrile in dichloromethane) gave 0.103 g (51% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.36 (6H, t, J=6.6 Hz, 2×CH3), 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.08-4.22 (4H, m, 2×OCH2), 4.78 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.45-7.52 (3H, m, aromatics), 7.65-7.72 (1H, m, aromatic), 8.67 (1H, broad t, NH). HRMS (ESI+) calculated for C28H34FN3O7P [M+H+]: 574.2118; found: 574.2126.

Workup

  1. customThe reaction mixture was then sealed
  2. washwashed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-b2dee4fa43dc4b488441bf6573b8077f
Source dataset
uspto-grants-2009_02
Patent number
US07491819B1

Reaction notes

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