Reaktion #638755

Reaktionsgleichung

(2R)-2-methylpyrrolidine (L)-tartrate

NaOH brine

product

7-Bromo-4-chloro-3-(2-chloro-ethyl)-cinnoline

2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

Na2CO3

→

title compound

7-(2,6-Dimethyl-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

Lösungsmittel

acetonitrile

toluene

toluene

isopropanol toluene

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturAfter cooling
2. 2
   Filtrationthe reaction mixture was filtered
3. 3
   workup.ADDITIONdiluted with 20 mL water
4. 4
   Extraktionextracted twice with 25 mL dichloromethane
5. 5
   Einengenconcentrated under reduced pressure
6. 6
   Temperaturthe resulting mixture was heated to 85° C. in a sealed tube for 48 hours
7. 7
   TemperaturUpon cooling
8. 8
   Einengenthe mixture was concentrated under reduced pressure
9. 9
   Sonstigepurified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol)

Vorschrift

A mixture of the product from Example 169C (0.100 g, 0.328 mmol), 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.077 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.012 g, 0.017 mmol), and 1 M Na2CO3 (0.820 mL, 0.820 mmol) in de-gassed isopropanol/toluene (5 mL, 1:1) was heated to 90° C. under a dry nitrogen atmosphere for 24 hours. After cooling, the reaction mixture was filtered, diluted with 20 mL water, extracted twice with 25 mL dichloromethane, and concentrated under reduced pressure. Next, (2R)-2-methylpyrrolidine (L)-tartrate (0.100 g, 0.425 mmol) was partitioned between toluene (0.5 mL) and 5M NaOH/brine (1:1, 1 mL total). The toluene phase (0.5 mL) was subsequently added to a solution of the above crude material in acetonitrile (3 mL) and the resulting mixture was heated to 85° C. in a sealed tube for 48 hours. Upon cooling, the mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 8.38 (m, 1H), 8.19 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.84 (dd, J=3, 9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 3.52-3.28 (m, 4H), 2.78-2.62 (m, 2H), 2.59 (s, 3H), 2.52 (s, 3H), 2.46-2.39 (m, 1H), 2.08-1.98 (m, 1H), 1.86-1.78 (m, 2H), 1.56-1.42 (m, 1H), 1.18 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 347.

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