Potassium Carbonate → (3R)-tert-Butyl 4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate

HRID 906473Notes

Reaction equation

HRID 906473 reaction equation
[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH2:42][C:43]([CH3:53])([CH3:52])[CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH:35]=[C:34]2[CH2:54][N:55]1[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C@H:56]1[CH3:68]>C(#N)C.O.[Cl-].[Na+].O>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[N:36]([CH2:42][C:43]([CH3:52])([CH3:53])[CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])[CH:35]=[C:34]4[CH2:54][N:55]3[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C@H:56]3[CH3:68])[CH:11]=2)=[O:23])[CH2:2][CH2:3]1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 21914563N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideHCID 67389792(3R)-tert-butyl 4-((6-bromo-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 86640984(3R)-tert-Butyl 4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylateYield 74.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolvent2×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
70 °C

Procedure

Pd-118 (0.688 g) was stirred in acetonitrile (80 mL) under nitrogen and after 5 min, N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9.26 g) was added. After 5 min, a solution of potassium carbonate (7.29 g) in water (80 mL) was added and after 10 min, a solution of (3R)-tert-butyl 4-((6-bromo-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate (16 g) in acetonitrile (80 mL) was added and the reaction heated at 70° C. for 1.5 h. After cooling to room temperature, brine (200 mL) was added and the mixture extracted with ethyl acetate (2×125 mL). The combined organics were dried (Na2SO4), filtered and the solvents evaporated. The residue was purified (SiO2 chromatography, eluting with 20%-35% ethyl acetate/2% triethylamine in isohexane) to give the subtitle compound (14.20 g).

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionthe mixture extracted with ethyl acetate (2×125 mL)
  3. dry with materialThe combined organics were dried (Na2SO4)
  4. filtrationfiltered
  5. customthe solvents evaporated
  6. customThe residue was purified
  7. wash(SiO2 chromatography, eluting with 20%-35% ethyl acetate/2% triethylamine in isohexane)

Sources & evidence

ORD record
ord-000708ce0d1b4e57b3e709df6d236b14
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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