Cesium carbonate → 1,1-dimethylethyl {(2S,3R)-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-8-azaspiro[4.5]dec-2-yl}carbamate

HRID 734232Notes

Reaction equation

HRID 734232 reaction equation
Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[OH:15][CH:16]1[CH2:20][C:19]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][CH:17]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:23]1[CH2:22][CH2:21][C:19]3([CH2:18][C@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C@H:16]([OH:15])[CH2:20]3)[CH2:25][CH2:24]1)=[N:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 454803208-Bromo-7-fluoro-2-methoxy-1,5-naphthyridineHCID 765808691,1-Dimethylethyl (3-hydroxy-8-azaspiro[4.5]dec-2-yl)carbamate

Product 1

HCID 578429281,1-dimethylethyl {(2S,3R)-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-8-azaspiro[4.5]dec-2-yl}carbamateYield 11%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a sealed tube, 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (500 mg, 1.96 mmol), 1,1-dimethylethyl (3-hydroxy-8-azaspiro[4.5]dec-2-yl)carbamate (530 mg, 1.96 mmol) [prepared according to Example 1], Pd2dba3 (121 mg, 0.117 mmol), rac-Binap (73 mg, 0.117 mmol), Cs2CO3 (1.30 g, 4.11 mmol) and 18-C-6 (52 mg, 0.196 mmol) in dioxane (20 mL) were combined and flushed with N2. After 15 min, the tube was sealed and heated to 100° C. while stirring rapidly. After 12 h, the solution was filtered, concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (92 mg, 11%) as an orange oil: LCMS (ES) m/e 447 (M+H)+.

Workup

  1. customflushed with N2
  2. customthe tube was sealed
  3. waitAfter 12 h
  4. filtrationthe solution was filtered
  5. concentrationconcentrated
  6. customthe residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH))

Sources & evidence

ORD record
ord-3561c829061e4506aec6d1d2ae57b299
Source dataset
uspto-grants-2009_09
Patent number
US07592334B2

Reaction notes

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