Cesium carbonate → 7-(3-tert-Butoxycarbonyl-phenyl)-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester

HRID 1052082Notes

Reaction equation

HRID 1052082 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4].[C:15]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:28])[CH:26]=3)[CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 18386959tert-Butyl 3-iodobenzoateHCID 84663902Methyl 5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylate

Product 1

HCID 866958807-(3-tert-Butoxycarbonyl-phenyl)-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl esterYield 44,591.199%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 1 L glass pressure vessel was charged with 5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (5.38 g, 0.028 mol) and 3-iodobenzoic acid tert-butyl ester (12.8 g, 0.042 mmol) in toluene (300 mL). The solution was stirred and sparged with argon for 10 min. Palladium(II)acetate (0.38 g, 0.00168 mol, 6 mole %) and cesium carbonate (18.3 g, 0.056 mol) were added and sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added and the vessel was sealed and heated at 100° C. overnight. HPLC analysis and TLC (ethyl acetate:hexane; 1:1) showed the reaction was complete. The reaction mixture was filtered and filter paper was washed with ethyl acetate (250 mL). The filtrate was washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×100 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top packed with hexane. The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32. All fractions checked by TLC. The product was eluted in fractions 19-28 to give the title compound (6.9 g, 67%) as a viscous oil. 1H NMR 60 MHz, (CDCl3), δ 9.0 (s, 1H), 8.6 (s, 1H), 7.4 (m. 5H), 4.5 (s, 2H), 4.0 (s, 3H), 3.6 (m, 4H), 1.7 (s, 9H).

Workup

  1. customsparged with argon for 10 min
  2. customsparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %)
  3. additionwas added
  4. customthe vessel was sealed
  5. filtrationThe reaction mixture was filtered
  6. filtrationfilter paper
  7. washwas washed with ethyl acetate (250 mL)
  8. washThe filtrate was washed with water (250 mL)
  9. customThe aqueous layer was separated
  10. extractionextracted with ethyl acetate (2×150 mL)
  11. washThe combined organic layers were washed with brine (3×100 mL)
  12. filtrationfiltered through 1PS filter paper
  13. concentrationconcentrated under reduced pressure
  14. customto give an oil
  15. customThe oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top
  16. washThe column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32
  17. washThe product was eluted in fractions 19-28

Sources & evidence

ORD record
ord-60bd06f6cd844dfaa51e2382a326c557
Source dataset
uspto-grants-2016_07
Patent number
US09388176B2

Reaction notes

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