Cesium carbonate → 6-Isopropoxy-5-methyl-nicotinic acid isopropyl ester

HRID 1908758Notes

Reaction equation

HRID 1908758 reaction equation
[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(O)=O.[Na+].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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[N:8][CH:7]=1)([CH3:3])[CH3:2]

Participants

9

Reactant 3

HCID 10796Cesium carbonateHCID 574072TrimethylboroxineHCID 22985641Isopropyl 5-chloro-6-isopropoxynicotinate

Product 1

HCID 670269796-Isopropoxy-5-methyl-nicotinic acid isopropyl esterYield 41.6%

Reagents, catalysts & solvents 5

HCID 83681Tris(1,1-dimethylethyl)phosphineCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-chloro-6-isopropoxy-nicotinic acid isopropyl ester (235 mg, 0.912 mmol) in dioxane (5 mL), 2,4,6-trimethyl-cyclotriboroxane (114 mg, 0.912 mmol), Cs2CO3 (386 mg, 1.19 mmol) and tri-tert.-butylphosphine (7.4 mg, 36 μmol) is added. The mixture is degassed and put under argon before Pd2(dba)3 (17 mg, 18 μmol) is added. The mixture is stirred at 100° C. for 18 h. The mixture is cooled to rt, diluted with water and sat. aq. NaHCO3-solution and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 9:1 to give 6-isopropoxy-5-methyl-nicotinic acid isopropyl ester (90 mg) as a colourless oil; LC-MS: tR=1.08 min; [M+1]+=238.08; 1H NMR (CDCl3): δ 1.35-1.41 (m, 12H), 2.20 (s, 3H), 5.20-5.30 (m, 1H), 5.37-5.48 (m, 1H), 7.95 (s, 1H), 8.67 (s, 1H). The title compound can be obtained by hydrolising 6-isopropoxy-5-methyl-nicotinic acid isopropyl ester according to the procedure given in step d) of the preparation of 5,6-diisobutyl-nicotinic acid.

Workup

  1. customThe mixture is degassed
  2. additionis added
  3. temperatureThe mixture is cooled to rt
  4. extractionextracted with EA
  5. extractionextract
  6. dry with materialis dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product is purified on prep

Sources & evidence

ORD record
ord-17b79141a5b5470594ca94eb5abfd537
Source dataset
uspto-grants-2013_12
Patent number
US08598208B2

Reaction notes

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