Water → N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 1502245

Reaktionsgleichung

Reaktionsgleichung von HRID 1502245
CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:27]1[C:28]([CH3:34])=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>[NH2:33][C:29]1[C:28]([CH3:34])=[C:27]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)[CH:32]=[N:31][CH:30]=1

Komponenten

8

Edukt 6

HCID 962WaterHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 70606795-Bromo-4-methylpyridin-3-amineHCID 67976378N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Produkt 1

HCID 57410129N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamideAusbeute 37 %

Reagenzien, Katalysatoren, Lösungsmittel 1

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

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a mixture of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.4 mg, 0.3530 mmol), 5-bromo-4-methylpyridin-3-amine (83.7 mg, 0.448 mmol), cesium carbonate (286.6 mg, 0.8796 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (19.2 mg, 0.0271 mmol) was added 1,4-dioxane (4 mL, 50 mmol) and water (0.4 mL, 20 mmol). The reaction was then stirred in a sealed vial at 100° C. for two hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted four times with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-15% MeOH in dichloromethane) followed by reverse phase HPLC purification and lyophilization to yield 41.3 mg (37%) of N-(7-(5-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=2.42, M+H=319.2, method=H; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.98 (s, 2H), 7.91 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.68-7.57 (m, 1H), 5.22 (s, 2H), 2.14-2.03 (m, 1H), 2.01 (s, 3H), 0.85 (dd, J=11.6, 6.1 Hz, 4H).

Aufarbeitung

  1. extractionextracted four times with dichloromethane
  2. dry with materialThe combined organic extracts were dried over MgSO4
  3. filtrationfiltered
  4. customevaporated in vacuo
  5. customThe crude residue was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-15% MeOH in dichloromethane)
  6. customfollowed by reverse phase HPLC purification and lyophilization

Quellen und Nachweise

ORD-Eintrag
ord-6a2d674be1334ab08025a247e2469015
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206175B2

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