Acetic Acid → tert-Butyl-(2R)-4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-2-(hydroxymethyl)piperazine-1-carboxylate

HRID 906417Notes

Reaction equation

HRID 906417 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18](=[O:26])[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH2:10][C@@H:9]1[CH2:36][OH:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]1([NH:41][C:42](=[O:60])[C:43]2[CH:48]=[C:47](B3OC(C)(C)C(C)(C)O3)[C:46]([CH3:58])=[C:45]([F:59])[CH:44]=2)[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:47]4[CH:48]=[C:43]([C:42](=[O:60])[NH:41][CH:38]5[CH2:39][CH2:40]5)[CH:44]=[C:45]([F:59])[C:46]=4[CH3:58])[CH:23]=3)[C:18](=[O:26])[NH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:36][OH:37])=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 11430Potassium CarbonateHCID 21914563N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideHCID 67389810tert-butyl-(2R)-4-((6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl)methyl)-2-(hydroxymethyl)piperazine-1-carboxylate

Product 1

HCID 67389794tert-Butyl-(2R)-4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-2-(hydroxymethyl)piperazine-1-carboxylateYield 27.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A solution of tert-butyl-(2R)-4-((6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl)methyl)-2-(hydroxymethyl)piperazine-1-carboxylate (Example 11e, 2.3 g) in DMF (20 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.24 g), Pd-118 (0.08 g) and potassium carbonate (0.86 g) under nitrogen. The resulting mixture was heated at 80° C. for 10 h. The reaction mixture was diluted with water (300 mL), acidified with acetic acid (to pH 5) and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography, elution with 1% AcOH in ethyl acetate) afforded the subtitle compound (0.60 g) as a solid.

Workup

  1. extractionextracted with ethyl acetate (300 mL)
  2. dry with materialThe organic was dried (MgSO4)
  3. filtrationfiltered
  4. customevaporated
  5. customto afford crude product
  6. customPurification (SiO2 chromatography, elution with 1% AcOH in ethyl acetate)

Sources & evidence

ORD record
ord-d23c5e27b39244ef99044997d6ca0c56
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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