1,4-Dioxane → 5-cyclopropylpyrazin-2-amine

Temperature

150 °C

To a microwave vial was charged with 5-bromopyrazin-2-amine (400 mg. 2.3 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g, 6.9 mmol), KOt-Bu (1M in t-BuOH, 9.2 mL), 1,4-dioxane (10 mL), and water (0.10 mL), and the mixture was purged with Argon, followed by addition of Palladium tetrakis (266 mg, 0.23 mmol) and final Argon purge, then the mixture was sealed and heated at 150° C. via microwave reactor for 20 min. To the reaction mixture was added 2nd portion of PalladiumTetrakis (266 mg) and the reaction was heated at 160° C. via microwave reactor for 20 min. The reaction mixture was filtered through a thin layer of Celite, and the filtrate was concentrated. The residue was triturated with EtOAc (6 mL), and the precipitates were removed via centrifugation and filtration. The EtOAc supernatant was back extracted with aqueous TFA solution (3×3 mL, TFA/water—1 mL/10 mL). The TFA solutions were combined, diluted with acetonitrile (10 mL), frozen and lyophilized to afford 5-cyclopropylpyrazin-2-amine in a yellow powder. The product after lyophilization was transferred to a vial, basified to pH>12 with sat. Na2CO3 (3 mL), extracted with EtOAc(4×6 mL), and the EtOAc extracts were combined, and concentrated and further dried under high vacuum, and final 5-cyclopropylpyrazin-2-amine free base was obtained (79 mg, 25.4% yield). LCMS (m/z): 136.1 (MH+), 0.30 min. 1H NMR (CD3OD) δ ppm 8.29 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 2.00-2.08 (m, 1H), 0.94-1.00 (m, 2H), 0.87-0.93 (m, 2H).

1. customthe mixture was purged with Argon
2. custompurge
3. customthe mixture was sealed
4. additionTo the reaction mixture was added 2nd portion of PalladiumTetrakis (266 mg)
5. temperaturethe reaction was heated at 160° C. via microwave reactor for 20 min
6. filtrationThe reaction mixture was filtered through a thin layer of Celite
7. concentrationthe filtrate was concentrated
8. customThe residue was triturated with EtOAc (6 mL)
9. customthe precipitates were removed via centrifugation and filtration
10. extractionThe EtOAc supernatant was back extracted with aqueous TFA solution (3×3 mL, TFA/water—1 mL/10 mL)
11. additiondiluted with acetonitrile (10 mL)
12. temperaturefrozen

ORD record

ord-c6388a7a0a634dd2b4ec59c4fe12c4b6

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242996B2