Water → N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 1502248Notes

Reaction equation

HRID 1502248 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:34])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.C([O-])(O)=O.[Na+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:34])=[C:21]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:20]=1

Participants

8

Reactant 6

HCID 962WaterHCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 160860894-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilineHCID 67974626N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 67974803N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamideYield 119%

Reagents, catalysts & solvents 1

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Catalyst

Conditions

Temperature
90 °C

Procedure

To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (1.053 g, 3.617 mmol), 5-amino-2-methylphenylboronic acid pinacol ester (1.2607 g, 5.4081 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.1311 g, 0.1852 mmol), and potassium carbonate (1.385 g, 10.02 mmol) was added 1,4-dioxane (20 mL, 200 mmol) and water (2 mL, 100 mmol). The reaction mixture was then heated at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted twice with dichloromethane. The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 1.3653 g (119%) of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=318.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (dd, J=8.5, 1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.60-6.49 (m, 2H), 4.93 (s, 2H), 2.14-2.02 (m, 4H), 0.85 (dd, J=12.4, 6.1 Hz, 4H).

Workup

  1. temperaturecooled to room temperature
  2. extractionextracted twice with dichloromethane
  3. dry with materialThe combined organics were dried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-f4b990e33d424e039696af04218fe2e2
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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