Potassium Carbonate → N-Cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide

HRID 906422Notes

Reaction equation

HRID 906422 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]2[CH:19]=[O:20].[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]4[CH:19]=[O:20])[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:22][CH2:23]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 21914563N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideHCID 866409686-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde2×

Product 1

HCID 86640963N-Cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamideYield 64.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

6-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26d 16.8 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.61 g), Pd-118 (1.619 g) and potassium carbonate (17.16 g) in DMF (140 mL) was heated to 70° C. for 4 h under nitrogen. The mixture was cooled, diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The separated organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 50 to 100% ethyl acetate in DCM) to give a solid, which was triturated with isohexane 1:1 diethyl ether (200 mL) for 1 h. The suspension was filtered and dried to give the subtitle compound (14.5 g) as a solid.

Workup

  1. customwas heated to 70° C. for 4 h under nitrogen
  2. temperatureThe mixture was cooled
  3. extractionextracted with ethyl acetate (300 mL)
  4. dry with materialThe separated organic layer was dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified
  8. wash(SiO2 chromatography, elution with 50 to 100% ethyl acetate in DCM)
  9. customto give a solid, which
  10. customwas triturated with isohexane 1:1 diethyl ether (200 mL) for 1 h
  11. filtrationThe suspension was filtered
  12. customdried

Sources & evidence

ORD record
ord-b5574e2c0aae4ef6984c78b79aa40b2b
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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