Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → N-(4-Fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide

HRID 348174Notes

Reaction equation

HRID 348174 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](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[OH:50][C:51]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:52]=1[CH2:53][NH2:54]>CN(C)C=O.CN(C1C=CN=CC=1)C>[F:59][C:57]1[CH:56]=[CH:55][C:52]([CH2:53][NH:54][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:51]([OH:50])[CH:58]=1

Participants

6

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210698432-(Aminomethyl)-5-fluorophenol hydrochlorideHCID 210698583-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid

Product 1

HCID 21070018N-(4-Fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideYield 64%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid, (1.50 g, 4.54 mmol) and HATU (2.07 g, 5.45 mmol) in anhydrous dimethylformamide was stirred for 20 minutes under a nitrogen atmosphere at room temperature. To the solution was added intermediate 135, 2-hydroxy-4-fluoro-benzylamine hydrochloride, (1.05 g, 5.9 mmol) followed by DMAP (1.39 g, 11.4 mmol), and the reaction mixture stirred at 60° C. for 90 minutes. The solvent was removed in vacuo and the crude residue purified by flash column chromatography (SiO2), eluting with 40%–60% ethyl acetate in hexanes to give the title compound (1.31 g, 64% yield) as a solid. 1H NMR (500 MHz, CDCl3) δ ppm: 9.69 (1H, br s), 8.18 (1H, t, J=6.3 Hz), 7.44 (2H, dd, J=6.6, 2.6 Hz), 7.30–7.35 (3H, m), 7.00 (1H, dd, J=8.2, 6.7 Hz), 6.68 (1H, dd, J=10.4, 2.4 Hz), 6.54 (1H, dt, J=8.2, 2.4 Hz), 5.29 (2H, s), 4.36 (2H, d, J=6.7 Hz), 3.97–4.05 (4H, m), 1.61 (6H, s).

Workup

  1. customThe solvent was removed in vacuo
  2. customthe crude residue purified by flash column chromatography (SiO2)
  3. washeluting with 40%–60% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-1d3651aa43704c8cb118fce134750401
Source dataset
uspto-grants-2007_02
Patent number
US07176196B2

Reaction notes

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