Potassium Carbonate → Tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate

HRID 906458Notes

Reaction equation

HRID 906458 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]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[CH:40]1([NH:43][C:44](=[O:62])[C:45]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[C:48]([CH3:60])=[C:47]([F:61])[CH:46]=2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:25])([CH3:24])[CH2:13][N:7]1[CH:6]=[C:5]([S:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:49]3[CH:50]=[C:45]([C:44](=[O:62])[NH:43][CH:40]4[CH2:41][CH2:42]4)[CH:46]=[C:47]([F:61])[C:48]=3[CH3:60])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 21914563N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideHCID 67390931Tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}piperidine-1-carboxylate

Product 1

HCID 67391538Tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylateYield 42.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A solution of tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}piperidine-1-carboxylate (Example 58c, 0.248 g) in DMF (4 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.124 g), Pd-118 (0.007 g) and potassium carbonate (0.107 g). The reaction was stirred at 80° C. for 6 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL), and the combined organics were washed with water (3×100 mL) and brine (3×100 mL). The organics were dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was purified (SiO2 chromatography, eluting with 10-50% ethyl acetate/isohexane) to afford the subtitle compound (0.123 g).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and water
  2. extractionThe aqueous was extracted with ethyl acetate (2×100 mL)
  3. washthe combined organics were washed with water (3×100 mL) and brine (3×100 mL)
  4. dry with materialThe organics were dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude product was purified
  8. wash(SiO2 chromatography, eluting with 10-50% ethyl acetate/isohexane)

Sources & evidence

ORD record
ord-3b640089769a4ad5a30265088b536eb9
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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